내장성 통증 visceral pain 탐구 2024

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Reviews in Basic and Clinical Gastroenterology and HepatologyVolume 166, Issue 6p976-994June 2024Open access

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Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments

Alexander C. Ford1,2,∗ ∙ Stephen Vanner3,∗ ∙ Purna C. Kashyap4 ∙ Yasmin Nasser5 ynasser@ucalgary.ca

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Abstract

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

초록 

만성 내장 통증은 

염증성 장 질환이나 뇌-장 상호작용 장애와 같은 

소화기 질환을 가진 환자들이 의료 도움을 찾는 가장 흔한 이유 중 하나입니다. 

이는 환자에게 심각한 부담을 초래하며, 

불안, 우울증, 삶의 질 저하, 사회적 기능 장애와 연관되어 있으며, 

사회에 직접적 및 간접적 의료 비용 증가를 초래합니다. 

불행히도, 

만성 내장 통증의 진단과 치료는 

근본적인 병리생리학적 기전에 대한 이해가 불완전하기 때문에 어렵습니다. 

이 리뷰에서는 

말초 통증 신호전달과 말초 통증 경로의 감작을 유발하는 

특정 생리적 및 병리생리학적 전임상 기전에 대한 최근 진전을 강조합니다. 

우리는 치료 접근법으로 전환된 전임상 메커니즘에 초점을 맞추고, 

임상 시험에서 도출된 만성 내장 통증의 이러한 메커니즘을 대상으로 한 

치료 방향을 위한 현재의 증거 기반을 요약합니다. 

만성 내장 통증의 효과적인 관리는 환자의 삶의 질에 있어 여전히 중요한 과제입니다. 

말초 통증 메커니즘에 대한 깊은 이해는 새로운 치료적 개입의 기반을 제공할 수 있습니다.

1.  

Abbreviations used in this paper

1. HT (5-hydroxytryptamine)
2. CB1 (cannabinoid receptor 1)
3. cGMP (guanosine 3′,5′-cyclic monophosphate)
4. DGBI (disorders of gut-brain interaction)
5. DOR (δ-opioid receptor)
6. FD (functional dyspepsia)
7. FDA (Food and Drug Administration)
8. FMT (fecal microbial transplant)
9. FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols)
10. GABA (γ-aminobutyric acid)
11. GC-C (guanylate cyclase-C)
12. GPCRs (G protein-coupled receptors)
13. IBD (inflammatory bowel disease)
14. IBS (irritable bowel syndrome)
15. IBS-D (inflammatory bowel disease with diarrhea)
16. KOR (κ-opioid receptor)
17. MOR (μ-opioid receptor)
18. RCT (randomized controlled trial)
19. SCFA (short-chain fatty acid)
20. SNRI (serotonin norepinephrine reuptake inhibitor)
21. SSRI (selective serotonin reuptake inhibitor)
22. TCA (tricyclic antidepressant)
23. TRP (transient receptor potential)
24. TRPV1 (transient receptor potential vanilloid 1)
25. US (United States)

Pain, defined as an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage, can be acute or chronic.1 It can originate from somatic (muscle, bone, or soft tissue) or visceral (thoracic, abdominal, or pelvic organs) structures.1 Visceral pain is one of the most challenging clinical conditions facing patients and their health care providers. It is extremely common. Abdominal pain is a key reason that patients with gastrointestinal disorders, such as inflammatory bowel disease (IBD) or disorders of gut-brain interaction (DGBI), including irritable bowel syndrome (IBS) or functional dyspepsia (FD), seek medical attention.2,3 More than 70% of patients with IBD experience abdominal pain during an acute flare,4 and between 20% and 60% report chronic abdominal pain.5 Chronic visceral pain is a hallmark of some DGBI, which affect up to 40% of adults, primarily women, worldwide.6

The diagnosis and treatment of chronic visceral pain is difficult, largely because it is poorly localized and difficult to describe due to the relatively small density of nerve terminals in the viscera and the divergent projections into the spinal cord,7 and because the pathophysiology remains incompletely understood. Chronic visceral pain is, thus, a significant burden to patients and is associated with anxiety, depression, decreased quality of life, and increased direct and indirect health care costs.5,8,9 IBS alone is estimated to cost the United States (US) ∼US $350 million each year for outpatient clinic visits, not including diagnostic testing, medications, nonpharmacologic therapies, or indirect costs due to lost productivity.10 Unfortunately, these challenges have been further amplified by the opioid crises.11,12 This highlights the continued need for advances in understanding of the pathophysiology of visceral pain to enable both effective and safe therapies.

Chronic visceral pain is a disorder of the microbiota-gut-brain axis, and central and peripheral mechanisms both contribute to its pathogenesis (Figure 1). Triggers include stress, psychological comorbidities, such as anxiety or depression, diet, low-grade intestinal inflammation, and microbial dysbiosis.4,13–15 Most abdominal pain signaling originates from nociceptors (pain-sensitive neurons), called visceral primary afferent nerves, whose cell bodies lie in the dorsal root ganglia and which have pseudo-unipolar axons connecting the intestine and the spinal cord.16 Nociceptors synapse with second-order neurons in the thoracolumbar and lumbosacral spinal cord17 and thereafter with central ascending pain pathways. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways originating from the hypothalamus and midbrain.18

통증은

실제 또는 잠재적인 조직 손상과 연관되거나 이와 유사한 불쾌한 감각적 및 정서적 경험으로 정의되며,

급성 또는 만성일 수 있습니다.1

통증은 체성(근육, 뼈, 또는 연부 조직) 또는

내장(흉부, 복부, 또는 골반 장기) 구조에서 발생할 수 있습니다.1

내장 통증은 환자 및 의료진에게 직면하는

가장 어려운 임상적 상태 중 하나입니다. 매우 흔합니다.

복통은

염증성 장 질환(IBD)이나 장-뇌 상호작용 장애(DGBI)와 같은

위장관 질환을 가진 환자들이 의료 도움을 찾는 주요 원인입니다.2,3

IBD 환자의 70% 이상이 급성 발작 시 복통을 경험하며,4

20%에서 60%는 만성 복통을 보고합니다.5

만성 내장 통증은 일부 DGBI의 특징으로,

전 세계 성인의 최대 40%,

주로 여성에게 영향을 미칩니다.6

만성 내장 통증의 진단과 치료는

내장 신경 말단의 상대적으로 낮은 밀도와 척수로의 다양한 투사 경로로 인해

통증이 명확히 국소화되지 않고 설명하기 어렵기 때문에,7

그리고 병리생리학이 완전히 이해되지 않았기 때문에 어렵습니다.

만성 내장 통증은 환자에게 심각한 부담을 주며,

불안, 우울증, 삶의 질 저하, 직접적 및 간접적 의료 비용 증가와 연관되어 있습니다.5,8,9 IBS alone is estimated to cost the United States (US) ∼US $350 million each year for outpatient clinic visits, not including diagnostic testing, medications, nonpharmacologic therapies, or indirect costs due to lost productivity.10

불행히도 이러한 도전은 오피오이드 위기によって 더욱 악화되었습니다.11,12

이는 내장 통증의 병리생리학에 대한 이해를 진전시켜 효과적이고 안전한 치료법을 개발하기 위한 지속적인 필요성을 강조합니다.

만성 내장 통증은

미생물군집-장-뇌 축의 장애이며,

중추 및 말초 메커니즘이 병인에 기여합니다(그림 1).

원인은

스트레스, 불안이나 우울증과 같은 심리적 동반 질환,

식단, 경미한 장 염증, 미생물 불균형 등이 있습니다.4,13–15

대부분의 복통 신호는

내장 구심성 신경이라고 하는 통각 수용체(통증에 민감한 신경 세포)에서 시작되며,

이 신경 세포의 세포체는 후근 신경절에 위치하고 장과 척수를 연결하는 의사 단극성 축삭을 가지고 있습니다.16

Extrinsic primary afferent signalling in the gut.pdf

330.78KB

내장 감각 신경세포는 장 기능을 조절하는 반사 경로를 활성화하며, 포만감, 복부 팽만감, 메스꺼움, 불편감, 급박감 및 통증과 같은 중요한 감각을 유발합니다. 감각 신경세포는 중추 신경계로 연결되는 세 가지 서로 다른 해부학적 경로(미주 신경, 흉요추 신경, 요천추 신경)로 조직되어 있습니다. 내장 감각 신경세포에서 많은 이온 채널, 수용체 및 제2 신호 전달물질의 역할을 규명하는 데 놀라운 진전이 이루어졌지만, 이러한 신경세포의 종류가 몇 가지인지, 그리고它们이 어떻게 다른지 이해하는 기본적인 목표는 달성하기 어려웠습니다. 우리는 세 가지 경로에 있는 거의 모든 1차 구심성 뉴런을 설명하는 구조적으로 뚜렷하게 구별되는 5가지 유형의 감각 말단이 장 벽에 존재한다고 제안합니다. 이 5가지 주요 구조 유형의 말단은 각각 독특한 생리적 반응의 조합을 보이는 것으로 보입니다. 이러한 유형은 다음과 같습니다. 장 신경절에 있는 ‘신경절 내 층’ 말단, 상피하층에 위치한 ‘점막’ 말단, 점막근에 가까운 기계 감지 말단이 있는 ‘근육-점막’ 구심성, 평활근층 내에 말단이 있는 ‘근육 내’ 말단, 그리고 주로 혈관에 민감한 말단이 있는 ‘혈관’ 구심성입니다. ‘무음’ 구심성 신경은 자극에 반응하지 않는 ‘혈관’ 구심성 신경의 하위 집합으로, 염증 매개체에 의해 활성화될 수 있습니다. 외인성 감각 신경 세포는 다양한 위장 장애에 대한 표적 치료의 매력적인 초점입니다.

장 벽에 존재하는 5가지 유형의 감각 말단 구조가 설명되며, 완전성을 위해 장 내장성 원심성 신경세포(enteric viscerofugal neurons)도 포함됩니다. 전환 부위는 열린 원으로 표시되며, 신경전달물질 방출 부위는 열린 삼각형으로 표시됩니다. 혈관 구심성 신경은 가장 복잡한 구심성 신경으로, 벽내 및 벽외 혈관 주위 축삭과 장 신경절, 점막, 외근육 및 척추 전 신경절에 있는 부수 신경이 있습니다. 신경절 내 축삭은 주로 장 신경절에서 신경절 내 층상 말단을 제공합니다. 점막 구심성 신경은 점막하 점막을 자극합니다. 근육-점막 구심성 신경은 점막 깊은 곳, 점막근에 가까운 곳에 말단이 있으며, 근육 내 구심성 신경은 세로 및/또는 원형 근육층 내에 신경 말단이 있습니다. 약어: CM, 원형 근육; LM, 세로 근육; MP, 장 신경총

통각 수용체는

흉요추부와 요천추부 척수에서 2차 신경세포와 시냅스를 형성하며,

이후 중추 상승 통증 경로를 통해 전달됩니다.

척수 내 통각 신경전달은

시상하부와 중뇌에서 기원하는 하행 경로에 의해 조절됩니다.18

Figure viewer

Figure 1 Chronic visceral pain is a disorder of the gut-brain axis. Nociceptors have cell bodies that lie in the dorsal root ganglia (DRG) and pseudounipolar axons that connect the intestine and the spinal cord. These synapse with second-order neurons in the spinal cord and with central ascending pathways thereafter. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways. (Inset) At the level of the mucosa, nociceptive terminals are both mechanosensitive and chemosensitive and are stimulated by luminal factors (eg, microbial products and nutrients) as well as by host mediators released due to infection, inflammation, or tissue damage (eg, serotonin, histamine, proteases, chemokines, and cytokines).

그림 1 만성 내장 통증은 장-뇌 축의 장애입니다.

통각 수용체는 등쪽 신경절(DRG)에 세포체를 가지고 있으며, 장과 척수를 연결하는

가짜 단극성 축삭을 가지고 있습니다.

이 축삭은 척수 내의 2차 신경세포와 시냅스를 형성하며, 이후 중추 상승 경로를 통해 전달됩니다.

척수 내의 통각 신경전달은 하행 경로에 의해 조절됩니다. (삽입도) 점막 수준에서 통각 말단 신경은 기계적 자극과 화학적 자극에 모두 민감하며, 장 내강 요인(예: 미생물 대사산물 및 영양소) 및 감염, 염증, 조직 손상으로 인해 방출되는 호스트 매개체(예: 세로토닌, 히스타민, 프로테아제, 케모카인, 사이토킨)에 의해 자극됩니다.

These mediators can act indirectly via the epithelium/enterochromaffin cells or can stimulate nociceptors directly if there is a breakdown in the mucosal barrier. This results in sensitization of ion channels such as TRP, resulting in increased visceral pain.

Sensitization of nociceptors, defined as a decrease in the threshold for stimulation and an increase in the magnitude of the response,19 can occur peripherally, in the central nervous system, or both. This results in hyperalgesia, a heightened response to painful stimuli, and allodynia, which is pain arising from nonpainful stimuli.19 Central sensitization may also result in comorbid pain involving different organ systems,20 a discussion of which is beyond the scope of this review.

At the level of the periphery, nociceptive nerve terminals are found in muscle and serosa as well as in the mucosa.7 Nociceptors are mechanosensitive and are stimulated by stretch or distention.16 These actions are mediated by a variety of mechanosensitive ion channels, such as the transient receptor potential (TRP) receptors, including TRP vanilloid 1 (TRPV1) and 4, and TRP ankyrin 1, the 2-pore domain potassium channel family, the degenerin/epithelial sodium channel family, including the acid-sensing ion channels 1, 2, and 3, and the piezo-type mechanosensitive ion channel component 2 (Piezo-02).21,22

Nociceptors at the mucosal level are also chemosensitive and are stimulated by luminal factors, such as microbial products and nutrients, as well as by chemical mediators released during tissue infection, inflammation, or damage. These include bacterial toxins, neurotransmitters, proteases, bioactive amines, such as histamine, and serotonin, neurotrophins, adenosine-5′-triphosphate, chemokines, and cytokines (Figure 1, inset).13,23 Luminal products can either stimulate nociceptors directly, particularly if there is associated breakdown in the mucosal barrier as seen in both IBD and IBS,24,25 or indirectly via the epithelium or enteroendocrine cells.26

Chemical compounds and luminal products can, in turn, stimulate pronociceptive G protein-coupled receptors (GPCRs) or lead to increased expression‎ and activation of ion channels, such as TRP or voltage-gated sodium and calcium channels, or can decrease potassium channel activation and expression‎, resulting in peripheral sensitization. In turn, nociceptors can release neurotransmitters, such as substance P and calcitonin gene-related peptide, which augment the inflammatory response in the periphery and activate second-order neurons in the spinal cord, leading to neurogenic inflammation13,23 (Figure 1, inset).

Building on this pathophysiological framework, this review will focus on recent advances in visceral peripheral pain neurotransmission and mechanisms that result in sensitization of afferents in patients with IBD or painful DGBI. It will discuss specific physiologic and pathophysiologic preclinical peripheral mechanisms that have been translated into receptor-based treatment approaches for visceral pain in clinical trials. Some of these treatments have targeted advances in the physiology of nociceptors or intermediary cells, or both, whereas others target new understanding of pathophysiologic mechanisms of specific disorders.

이러한 매개체는 상피/엔테로크로마핀 세포를 통해 간접적으로 작용하거나,

점막 장벽의 손상이 발생하면 통각 수용체를 직접 자극할 수 있습니다.

이는 TRP와 같은 이온 채널의 감작을 유발하여

내장 통증이 증가합니다.

통각 수용체의 감작은

자극에 대한 역치 감소와 반응 강도 증가로 정의되며,19

말초, 중추 신경계, 또는 둘 다에서 발생할 수 있습니다.

이것은

통증 자극에 대한 과도한 반응인 과민증과

통증이 아닌 자극에서 발생하는 통증인 이형통을 유발합니다.19

중추 감작은

또한 다양한 장기 시스템에 걸친 동반 통증을 유발할 수 있으며,20

이에 대한 논의는 이 리뷰의 범위를 넘어섭니다.

주변 수준에서는 통각 신경 말단이 근육, 세로사, 점막 등에 존재합니다.7 통각 수용체는 기계적 자극에 민감하며, 신장이나 확장 자극에 의해 자극됩니다.16 이러한 작용은 일시적 수용체 잠재력(TRP) 수용체, TRP 반일린 1(TRPV1)과 4, TRP 안키린 1, 2-포어 도메인 칼륨 채널 가족, 데제네린/상피 나트륨 채널 가족(산성 감지 이온 채널 1, 2, 3 포함), 피에조형 기계감각 이온 채널 구성 요소 2(Piezo-02) 등이 포함됩니다.21,22

점막 수준의 통각 수용체는 또한 화학 감수성을 가지고 있으며,

미생물 산물 및 영양소와 같은 내강 인자뿐만 아니라

조직 감염, 염증 또는 손상 시 방출되는 화학 매개체에 의해 자극됩니다.

이에는

세균 독소, 신경전달물질, 프로테아제, 히스타민과 세로토닌 같은 생물활성 아민,

신경영양인자, 아데노신-5′-트리포스페이트, 케모카인, 사이토킨 등이 포함됩니다(그림 1, 삽입도).13,23

내강 제품은 점막 장벽의 손상이 동반되는 경우(IBD 및 IBS에서 관찰됨)24,25

특히 직접적으로 통각 수용체를 자극하거나,

상피세포나 장내 내분비 세포를 통해 간접적으로 자극할 수 있습니다.26

화학 물질과 장내 분비물은 차례로 통각 촉진성 G 단백질 결합 수용체(GPCR)를 자극하거나 TRP 또는 전압 의존성 나트륨 및 칼슘 채널과 같은 이온 채널의 발현 및 활성화를 증가시키거나, 칼륨 채널의 활성화 및 발현을 감소시켜 말초 감작화를 유발할 수 있습니다. 반면, 통각 수용체는 substance P 및 칼시토닌 유전자 관련 펩타이드와 같은 신경전달물질을 방출하여 말초에서의 염증 반응을 강화하고 척수 내 2차 신경세포를 활성화시켜 신경성 염증을 유발합니다.13,23 (그림 1, 삽입도).

이러한 병리생리학적 프레임워크를 바탕으로, 본 리뷰는 IBD 또는 통증이 있는 DGBI 환자에서 내장 말초 통증 신경 전달 및 구심성 감각의 민감화를 초래하는 메커니즘에 대한 최근의 진전을 중점적으로 다룰 것입니다. 또한, 임상 시험에서 내장 통증에 대한 수용체 기반 치료 접근법으로 전환된 특정 생리학적 및 병리생리학적 전임상 말초 메커니즘에 대해 논의할 것입니다. 일부 치료법은 통각 수용체나 중간 세포의 생리학적 진전에 초점을 맞췄으며, 다른 치료법은 특정 질환의 병리생리학적 메커니즘에 대한 새로운 이해를 목표로 합니다.

Mechanistic Advances and the Resulting Therapies

Guanylate Cyclase-C and Visceral PainGuanylate cyclase-C pharmacology and preclinical studies

The enterocyte receptor guanylate cyclase-C (GC-C) plays an essential role in fluid secretion, barrier function, and nociception. Drugs such as linaclotide and plecanatide have taken advantage of this homeostatic system to treat visceral pain. GC-C is found on the apical surface of enterocytes throughout the gastrointestinal tract and is activated by the paracrine hormones uroguanylin and guanylin.27 Activation of GC-C triggers enzymatic conversion of guanosine-5ʹ-triphosphate to guanosine 3′,5′-cyclic monophosphate (cGMP), which in turn regulates activity of the apical cystic fibrosis transmembrane conductance regulator, leading to increased luminal chloride and bicarbonate secretion and a secondary increase in intestinal motility.27 Genetic mutations in the guanylate cyclase 2C gene (GUCY2C) have been found in patients with congenital secretory diarrhea28 and may predispose patients to IBD,29 whereas dysregulated GC-C expression‎ has been implicated in the pathophysiology of both IBD30 and IBS.31 Sex differences have not been reported.32

Epithelial GC-C signaling has a key role in nociception. Linaclotide, a minimally absorbed GC-C agonist, decreased the visceral motor response to colorectal distention in both acute colitis and stress-induced models of visceral hypersensitivity. The effects of linaclotide were abolished in GC-C–knockout animals, confirm‎ing its specificity.33 Linaclotide34 or direct application of cGMP34,35 to an ex vivo preparation of nociceptor afferents decreased response to circumferential stretch in control animals as well as in acute colitis35 and in postinflammatory34 models of visceral pain. GC-C expression‎ was not found on nociceptors,34,35 suggesting its antinociceptive effects were indirect. Indeed, linaclotide34 and uroguanylin35 both stimulated cGMP release from cultured epithelial cells.35 The effects of linaclotide were abolished in ex vivo preparations where the mucosa was removed.34

These studies suggest that epithelial GC-C activation causes basolateral cGMP secretion, which decreases nociceptor activity, providing a biological mechanism for the clinical effects of GC-C agonists. We note that a recent study has challenged the dogma that enterocyte-derived cGMP is the main antinociceptive mediator of GC-C activation,36 as discussed in section 6.

기전적 진전과 결과적 치료법

구아닐산 사이클레이즈-C와 내장 통증구아닐산 사이클레이즈-C의 약리학 및 전임상 연구

장 상피 세포 수용체인 구아닐산 사이클레이스-C(GC-C)는 체액 분비, 장벽 기능, 통각에 필수적인 역할을 합니다. 리나클로티드와 플레카나티드와 같은 약물은 이 항상성 시스템을 활용해 내장 통증을 치료합니다. GC-C는 소화관 전체의 장 상피 세포의 아피칼 표면에 존재하며, 파라크린 호르몬인 우로구아니린과 구아니린에 의해 활성화됩니다.27 GC-C의 활성화는 구아노신-5ʹ-트리포스페이트를 구아노신 3′,5′-사이클릭 모노포스페이트(cGMP)로 전환하는 효소적 반응을 유발하며, 이는 차례로 상피 세포의 상피성 낭포성 섬유증 막 전도 조절자(CFTR)의 활성을 조절하여 장 내강 내 염화물 및 중탄산염 분비를 증가시키고, 이는 다시 장 운동성을 증가시킵니다.27 구아닐산 사이클라제 2C 유전자(GUCY2C)의 유전적 변이가 선천성 분비성 설사 환자에서 발견되었으며, 이는 IBD 발병 위험을 증가시킬 수 있습니다.29 반면 GC-C 발현의 조절 장애는 IBD30 및 IBS의 병리생리학에 관여하는 것으로 알려져 있습니다.31 성별 차이는 보고되지 않았습니다.32

상피 GC-C 신호전달은 통각에 핵심적인 역할을 합니다. 최소 흡수형 GC-C 작용제인 리나클로티드는 급성 대장염 및 스트레스 유발성 내장 과민증 모델에서 대장 확장 시 내장 운동 반응을 감소시켰습니다. 리나클로티드의 효과는 GC-C 결핍 동물에서 사라졌으며, 이는 리나클로티드의 특이성을 확인했습니다.33 리나클로티드34 또는 cGMP34를 통각 수용체 구심성 신경의 생체 외 제제에 직접 적용한 결과, 대조군 동물과 급성 대장염35 및 염증 후34 내장 통증 모델에서 원주 방향의 신장에 대한 반응이 감소했습니다. GC-C 발현은 통각 수용체에서 발견되지 않았습니다.34,35 이는 그 항통각 효과가 간접적임을 시사합니다. 실제로, 리나클로티드34와 우로구아니린35는 모두 배양된 상피 세포에서 cGMP 방출을 자극했습니다.35 리나클로티드의 효과는 점막이 제거된 체외 준비물에서 소실되었습니다.34

이 연구들은 상피 세포의 GC-C 활성화가 기저측 cGMP 분비를 유발하여 통각 수용체 활성을 감소시킨다는 것을 보여주며, 이는 GC-C 작용제의 임상적 효과에 대한 생물학적 메커니즘을 제공합니다. 우리는 최근 연구가 GC-C 활성화의 주요 항통각 매개체로 장 상피 세포에서 유래한 cGMP라는 통설을 도전했다는 점을 지적합니다.36 이는 제6절에서 논의되었습니다.

Clinical trials

Linaclotide and plecanatide have been tested in multiple randomized controlled trials (RCTs) in IBS with constipation, summarized in a prior meta-analysis (for summary of all trials discussed see Table 1).37 Both were more efficacious than placebo in the effect on abdominal pain, according to the US Food and Drug Administration (FDA)-recommended end point for abdominal pain in IBS with constipation, consisting of a ≥30% improvement from baseline for ≥50% of weeks. However, delayed-release forms of linaclotide, developed based on the premise that ileocecal delivery of the drug targets abdominal pain without affecting bowel habit, were not superior to placebo over most abdominal pain measures in a phase II RCT.38

임상 시험

Linaclotide와 plecanatide는 변비 동반 IBS에서 다수의 무작위 대조 시험(RCT)에서 테스트되었으며, 이전 메타분석에서 요약되었습니다(모든 시험의 요약은 Table 1 참조).37 두 약물은 미국 식품의약국(FDA)이 IBS와 변비 환자의 복통 평가 지표로 권장한 기준(기저치 대비 ≥30% 개선이 ≥50%의 주에서 달성됨)에 따라 복통 완화 효과에서 위약보다 유의미하게 우수했습니다. 그러나 장 운동 습관에 영향을 주지 않으면서 복통을 표적으로 삼기 위해 장의 회맹부로 약물을 전달하는 원리에 기반해 개발된 리나클로티드의 지연 방출 제형은 제2상 RCT에서 대부분의 복통 측정 항목에서 위약보다 우월하지 않았습니다.38

Treatment studiedConditionNo. of studiesNo. of patientsComparatorReported effect

Linaclotide, 290 μg q.d.	IBS-C	3 RCTs summarized in a meta-analysis37	2447	Placebo	RR of abdominal pain persistence = 0.79 (95% CI, 0.73–0.85)
Plecanatide, 6 mg or 3 mg q.d.	IBS-C	2 RCTs summarized in a meta-analysis37	2194	Placebo	RR of abdominal pain persistence = 0.84 (95% CI, 0.78–0.90) and 0.87 (95% CI, 0.81–0.93), respectively
Loperamide	IBS-D Unselected patients with IBS	2 RCTs54,55	24 60	Placebo Placebo	Abdominal pain score 3.0 vs −0.14, P < .05 2.2 days with abdominal pain vs 8.3 days, P < .01
Eluxadoline, 100 mg or 75 mg b.i.d.	IBS-D	4 RCTs summarized in a meta-analysis56	2758	Placebo	RR of abdominal pain persistence = 0.89 (95% CI, 0.83–0.96) and 0.95 (95% CI, 0.88–1.04), respectively
Psyllium (up to 10 g/d)	Unselected patients with IBS	2 RCTs89,90	80 178	Placebo Placebo	Abdominal pain mild or absent in 52.5% vs 57.5%, N/S RR of adequate relief of abdominal pain at 1, 2, and 3 months = 1.60 (95% CI, 1.13–2.26), 1.44 (95% CI, 1.02–2.06), and 1.36 (95% CI, 0.90–2.04), respectively
Bran (up to 10 g/d)	Unselected patients with IBS	1 RCT90	190	Placebo	RR of adequate relief of abdominal pain at 1, 2, and 3 months = 1.13 (95% CI, 0.81–1.58), 1.22 (95% CI, 0.86–1.72), and 1.70 (95% CI, 1.12–2.57), respectively
Low FODMAP diet	IBS IBD	12 RCTs summarized in a meta-analysis91 2 RCTs92,93	914 52 89	BDA dietary advice Habitual diet Sham diet Sham diet Habitual diet	RR of abdominal pain persistence = 0.78 (95% CI, 0.57–1.06) RR of abdominal pain persistence = 0.72 (95% CI, 0.47–1.10) RR of abdominal pain persistence = 0.51 (95% CI, 0.30–0.87) Abdominal pain severity score 22 vs 30, P = .098 and 36 days with abdominal pain vs 38 days, P = .78 OR for improvement in abdominal pain frequency = 2.97 (95% CI, 1.12–7.89)
Rifaximin, 550 mg t.i.d. for 2 weeks	Nonconstipated IBS	2 RCTs summarized in a meta-analysis56	1260	Placebo	RR of abdominal pain persistence = 0.95 (95% CI, 0.89–1.01
FMT	IBS with bloating Unselected patients with IBS UC	2 RCTs96,97 1 RCT98	62 165 20	Placebo Placebo Usual treatment	Abdominal pain score 2.80 vs 3.88 at baseline with FMT, P = .001, compared with 3.57 vs 3.79 at baseline with usual treatment, P = .205 Abdominal pain score 166.8 and 186.3 posttreatment with 60 mg and 30 mg FMT, respectively, vs 307.0 with placebo, P < .001 Abdominal pain score 0.9 vs 4.5 at baseline with FMT, P = .026, compared with 1.8 vs 4.9 at baseline with usual treatment, N/S
Gelsectan	IBS-D	1 RCT99	60	Placebo	Number of patients with totally to slightly unacceptable abdominal pain reduced from 67% at baseline to 0% at 4 weeks with gelsectan vs 83% to 60% with placebo, statistical significance not reported
Probiotics Combination probiotics Lactobacillus-containing strains Saccharomyces cerevisiae I-3856 Bifidobacterium-containing strains Bacillus-containing strains	All in unselected patients with IBS	32 RCTs100 11 RCTs100 5 RCTs100 3 RCTs100 3 RCTs100	3469 1183 1482 389 212	Placebo Placebo Placebo Placebo Placebo	RR of abdominal pain persistence = 0.72 (95% CI, 0.64–0.82) RR of abdominal pain persistence = 0.59 (95% CI, 0.45–0.76) RR of abdominal pain persistence = 0.64 (95% CI, 0.45–0.90) RR of abdominal pain persistence = 0.78 (95% CI, 0.64–0.95) RR of abdominal pain persistence = 0.33 (95% CI, 0.23–0.47)
Ketotifen (titrated from 2 mg to 6 mg b.i.d.)	Unselected patients with IBS	1 RCT109	60	Placebo	7% of patients reporting severe abdominal pain vs 28%, P = .02
Ebastine 20 mg o.d.	Unselected patients with IBS Nonconstipated IBS	1 RCT110 1 RCT111	55 202	Placebo Placebo	Relief of abdominal pain in 41% vs 20%, P = .19 ≥30% improvement in abdominal pain in 37% vs 25%, P = .081
Disodium cromoglycate, 600 mg/d	IBS-D	1 RCT112	43	No treatment	≥50% improvement in abdominal pain in 77% vs 28%, P = .002
Peppermint oil (usually 2 capsules t.i.d.)	Unselected patients with IBS	7 RCTs summarized in a meta-analysis119	748	Placebo	RR of abdominal pain persistence = 0.76 (95% CI, 0.62–0.93)
Red pepper (capsaicin)	Unselected patients with IBS FD	1 RCT120 1 RCT121	50 30	Placebo Placebo	Abdominal pain score 1.9 vs 2.7 at baseline with red pepper, compared with 2.3 vs 2.4 at baseline with placebo, reported as “statistically significant” Abdominal pain score 1.61 posttreatment vs 2.37, P < .05
Alosetron, 1 mg b.i.d.	IBS-D	6 RCTs summarized in a meta-analysis56	2606	Placebo	RR of abdominal pain persistence = 0.83 (95% 0.78–0.88)
Ramosetron, 5 μg or 2.5 μg o.d.	IBS-D	5 RCTs summarized in a meta-analysis56	1928	Placebo	RR of abdominal pain persistence = 0.82 (95% CI, 0.75–0.89) and 0.75 (95% CI, 0.65–0.85), respectively
Ondansetron, 12 mg q.d, bimodal release or titrated up or down from 4 mg o.d.	IBS-D	3 RCTs summarized in a meta-analysis127	327	Placebo	RR of abdominal pain persistence = 0.95 (95% CI, 0.74–1.20)
Tegaserod, 6 mg b.i.d.	IBS-C FD	Pooled analysis of 4 RCTs128 2 RCTs129	2886 1360 1307	Placebo Placebo Placebo	OR for abdominal pain response = 1.38 (95% CI, 1.14–1.67) Abdominal pain response rate 44.9% vs 40.0%, P = .027 Abdominal pain response rate 44.0% vs 42.3%, P = .51
SSRIs (eg, escitalopram, 10 mg o.d.)	Unselected patients with IBS FD	5 RCTs summarized in a meta-analysis132 1 RCT133	262 195	Placebo Placebo	RR of abdominal pain persistence = 0.82 (95% CI, 0.58–1.16) Upper abdominal pain score 1.4 posttreatment vs 1.2, N/S
TCAs (eg, amitriptyline, 10–30 mg o.d., or imipramine, 50 mg o.d.)	Unselected patients with IBS FD	4 RCTs summarized in a meta-analysis132 1 RCT134 2 RCTs133,135	171 463 194 107	Placebo Placebo Placebo Placebo	RR of abdominal pain persistence = 0.53 (95% CI, 0.34–0.83) OR for ≥30% improvement in abdominal pain = 1.66 (95% CI, 1.12–2.46) Upper abdominal pain score 1.1 post-treatment vs 1.2, N/S Epigastric pain score 0.96 vs 1.24 at baseline with imipramine, P = .026, compared with 0.96 vs 1.13 at baseline with placebo, P = .13
SNRIs (eg., venlafaxine 150 mg o.d.)	Unselected patients with IBS	1 RCT136	30	Placebo	Frequency of abdominal pain or discomfort score 3.87 vs 4.93, P = .03
Oloroinab, 10 mg to 100 mg t.i.d.	IBS with abdominal pain Crohn’s disease with abdominal pain	1 RCT147 1 randomized, open-label study148	273 14	Placebo N/A	56.5%, 59.7%, and 56.7% of 10 mg, 25 mg, and 50 mg t.i.d., respectively, achieved a ≥30% improvement in abdominal pain vs 52.9% with placebo, N/S
					Change in abdominal pain score from baseline of −4.61 with 25 mg t.i.d. and −4.57 with 100 mg t.i.d.
Pregabalin, 75 mg o.d., or titrated up from 75 mg b.i.d.	Unselected patients with IBS FD	1 RCT154 1 RCT155	85 72	Placebo Placebo	Abdominal pain score 28 posttreatment vs 40, P = .008 Epigastric pain score 3.0 posttreatment vs 4.0, P = .01

Table 1

Summary of Evidence for Efficacy of Available Treatments Directed Against Peripheral Mechanisms of Abdominal Pain in Their Effect on Abdominal Pain as an End Point

BDA, British Dietetic Association; b.i.d., twice daily; CI, confidence interval; IBS-C, IBS with constipation; N/A, not applicable; N/S, not significant; o.d., once daily; OR, odds ratio; q.d., once daily; RR, relative risk; t.i.d., 3 times daily.

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Peripherally Acting Opioids and Visceral Pain

Pharmacology and preclinical studies

Opioids signal through 4 GPCRs: μ-opioid receptors (MORs), δ-opioid receptors (DORs), κ-opioid receptors (KORs), and nociceptin opioid receptors.39 The analgesic effect of conventional opioids can be strong (eg, oxycodone, morphine) or weak (eg, codeine) and predominantly result from activation of MORs, although DORs and KORs also play a role. On nociceptors, these receptors trigger GPCR-Gi/o protein signaling leading to the recruitment of multifunctional intracellular proteins, called β-arrestins, and sustained signaling by endosomes.40 This signaling modulates ion channels and, ultimately, inhibits action potential firing. Receptor expression‎ is increased in inflammatory conditions, including active IBD, possibly leading to altered signaling.41

Conventional opioids can exhibit potent analgesic actions, particularly for acute pain, but are limited by their adverse effect profile, including cognitive impairment, respiratory depression, nausea, constipation, and addictive potential.42 Analgesic tolerance leads to dose escalation and consequently greater risk of these potentially life-threatening adverse effects. Dose escalation is also implicated in the development of a paradoxical switch in signaling, leading to opioid-induced hyperalgesia, a poorly understood condition.43 The opioid crisis has hastened the search for safer alternatives, including peripherally restricted opioids that lack addictive potential and central adverse effects such as respiratory depression and cognitive impairment.

Strategies to develop peripherally acting opioids are being explored to identify safe, yet effective, analgesics for visceral pain. Access to the central nervous system can be restricted, for example, by creating charged molecules, and several compounds display peripheral analgesic actions,44,45 including loperamide, a MOR agonist.46 To date, however, these do not exhibit sufficient analgesic effects to be clinically useful to treat visceral pain.

Another strategy is to target opioid receptor heterodimers, such as eluxadoline,47 a MOR agonist and DOR antagonist with weak affinity for KORs. MORs and DORs are coexpressed on nociceptors innervating the intestine, and eluxadoline shows high binding affinity for MOR/DOR heterodimers in cell assays48 and functional interaction between receptors. However, there has been sparse mechanistic study in whole-animal models to clarify the role of this interaction further.49

There are other promising strategies to develop safe opiates, such as enhancing endogenous opioids (eg, enkephalinase inhibitors), by developing pH-sensitive opioid analogues,50 which are only active at sites of inflammation and thus lack the adverse effect profile and addictive potential of conventional opioids. Combinations of subthreshold opioids and cannabinoid receptor 1 (CB1) agonists can provide strong analgesia51 without adverse effects. Novel delivery systems using nanoparticles of between 1 and 100 nm in diameter, containing opioid cargoes,52 target intracellular signaling in endosomes and can be delivered intrarectally to act locally within the inflamed colon. To date, most of these strategies are based on preclinical studies and none have been tested adequately in humans. Finally, female rodents are less sensitive to opiate analgesia,53 and whether these strategies have sex-specific effects would be important to eval‎uate.

말초 작용 오피오이드와 내장 통증

약리학 및 전임상 연구

오피오이드는 4개의 GPCR을 통해 신호 전달합니다:

μ-오피오이드 수용체 (MORs),

δ-오피오이드 수용체 (DORs),

κ-오피오이드 수용체 (KORs), 및

노시셉틴 오피오이드 수용체.39

전통적인 오피오이드의 진통 효과는 강할 수 있습니다 (예: 옥시코돈, 모르핀) 또는 약할 수 있습니다 (예: 코데인)이며, 주로 MORs의 활성화에서 비롯되지만 DORs와 KORs도 역할을 합니다. 통각 수용체에서 이러한 수용체는 GPCR-Gi/o 단백질 신호전달을 유발하여 다기능 세포 내 단백질인 β-arrestins의 모집과 엔도좀을 통한 지속적 신호전달을 유도합니다.40 이 신호전달은 이온 채널을 조절하며, 최종적으로 활동 전위 발사를 억제합니다. 수용체 발현은 염증 상태, 특히 활동성 IBD에서 증가할 수 있으며, 이는 신호전달의 변화를 초래할 수 있습니다.41

전통적인 오피오이드는 급성 통증에 강력한 진통 효과를 나타내지만,

인지 장애, 호흡 억제, 메스꺼움, 변비, 중독 가능성 등

부작용 프로파일로 인해 제한됩니다.42

진통 내성은 용량 증가를 초래하며, 이는 잠재적으로 생명을 위협하는 부작용의 위험을 높입니다. 용량 증가 는 신호 전달의 역설적 전환을 유발해 오피오이드 유발 과민증(아직 잘 이해되지 않은 상태)으로 이어질 수 있습니다.43 오피오이드 위기는 중독 가능성과 호흡 억제, 인지 장애와 같은 중추 신경계 부작용이 없는 말초 제한형 오피오이드를 포함한 더 안전한 대안 개발을 가속화했습니다.

말초 작용 오피오이드 개발 전략은 내장 통증에 안전하면서도 효과적인 진통제를 식별하기 위해 탐구되고 있습니다. 중추 신경계 접근을 제한하는 방법으로는 전하를 띤 분자를 생성하는 것이 있으며, 여러 화합물이 말초 진통 효과를 나타냅니다.44,45 예를 들어 MOR 작용제인 로페라미드입니다.46 그러나 현재까지 이러한 화합물은 내장 통증 치료에 임상적으로 유용한 충분한 진통 효과를 보여주지 못했습니다.

또 다른 전략은 오피오이드 수용체 이량체(heterodimer)를 표적으로 삼는 것으로, 엘루사돌린(eluxadoline)47과 같은 MOR 작용제이자 DOR 길항제(KOR에 대한 친화력이 약함)가 이에 해당됩니다. MOR과 DOR은 장을 신경 분포하는 통각 수용체에 공동 발현되며, 엘루사돌린은 세포 실험에서 MOR/DOR 이량체에 대한 높은 결합 친화성을48 보이고 수용체 간의 기능적 상호작용을 나타냅니다. 그러나 이 상호작용의 역할을 명확히 하기 위한 전체 동물 모델에서의 기전 연구는 부족합니다.49

안전한 오피오이드 개발을 위한 다른 유망한 전략으로는 내인성 오피오이드(예: 엔케팔리나제 억제제)를 강화하거나, 염증 부위에서만 활성화를 보이는 pH 감응성 오피오이드 유사체를 개발하는 것이 있습니다.50 이러한 유사체는 전통적 오피오이드의 부작용 프로파일과 중독 가능성을 갖지 않습니다. 아편 유사체와 대마초 수용체 1(CB1) 작용제의 조합은 부작용 없이 강력한 진통 효과를 제공할 수 있습니다.51 지름 1~100nm의 나노입자에 아편 유사체를 함유한 새로운 전달 시스템은52 엔도좀 내 세포 내 신호전달을 표적화하며, 염증성 대장에 국소적으로 작용하기 위해 직장 내 투여가 가능합니다. 현재까지 이러한 전략의 대부분은 전임상 연구에 기반을 두고 있으며, 인간에서 충분히 테스트되지 않았습니다. 마지막으로, 암컷 설치류는 오피오이드 진통제에 덜 민감하며,53 이러한 전략이 성별 특이적 효과를 가지는지 평가하는 것이 중요합니다.

Clinical trials

Few trials have been conducted with new opioid-related drugs in visceral pain, largely due to the negative impact of the opioid crisis. Despite widespread use of loperamide in clinical practice, there is little evidence for this. One 13-week RCT, recruiting patients with IBS with diarrhea (IBS-D), reported pain scores were significantly lower with loperamide.54 In a second 3-week trial that recruited IBS of all subtypes, the number of painful days was reduced significantly with loperamide, but only in patients with alternating bowel habit.55 Both trials used historical definitions of IBS, did not conform to guidance for design of treatment trials in DGBI, and many participants did not report abdominal pain at all. More rigorous trials of loperamide are needed, although it is unlikely these will ever be conducted.

In contrast, eluxadoline has been tested rigorously in phase III RCTs at 2 doses, 75 mg or 100 mg twice daily, with data pooled in a prior meta-analysis.56 Only 100 mg twice daily was superior to placebo for the FDA-recommended end point for abdominal pain, but benefit was modest. In addition, there have been safety issues, with episodes of acute pancreatitis and sphincter of Oddi dysfunction reported.

임상 시험

내장 통증에 대한 새로운 오피오이드 관련 약물의 임상 시험은 오피오이드 위기の影響으로 인해 거의 진행되지 않았습니다. 임상에서 널리 사용되는 로페라미드에 대한 증거는 제한적입니다. IBS-D 환자를 대상으로 한 13주 RCT에서 로페라미드가 통증 점수를 유의미하게 감소시켰다는 보고가 있습니다.54 두 번째 3주 임상시험에서 모든 하위 유형의 IBS 환자를 대상으로 한 결과, 로페라미드 투여 시 통증 발생 일수가 유의미하게 감소했지만, 이는 배변 습관이 변동되는 환자군에서만 관찰되었습니다.55 두 임상시험 모두 IBS의 역사적 정의에 따라 진행되었으며, DGBI 치료 임상시험 설계 지침에 부합하지 않았고, 많은 참가자가 복통을 전혀 보고하지 않았습니다. 로페라미드의 더 엄격한 임상시험이 필요하지만, 이러한 연구가 진행될 가능성은 낮습니다.

반면, 엘루사돌린은 2용량(75mg 또는 100mg 하루 두 번)으로 진행된 3상 무작위 대조 시험(RCT)에서 엄격히 평가되었으며, 이전 메타분석에서 데이터가 통합되었습니다.56 FDA가 권장한 복통 평가 지표에서 100mg 하루 두 번 투여만 위약보다 우월했지만, 효과는 미미했습니다. 또한 안전성 문제도 보고되었으며, 급성 췌장염과 오디 괄약근 기능 장애 사례가 보고되었습니다.

The Microbiome and Visceral Pain

Advances in pathophysiology

The involvement of gut microbiota in the development of visceral pain is largely based on preclinical studies measuring pain thresholds after transfer of human stool microbiota into germ-free rodents or administration of live biotherapeutics (probiotics) or antibiotics, or both, in rodent models. For instance, germ-free rats colonized with stool microbiota from individuals with IBS display decreased pain thresholds in response to rectal distention.57 Further insights have been gained from studies involving gnotobiotic mice, revealing the role of commensal microbes in maintaining normal excitability of gut intrinsic neurons.58

Perturbing the gut microbiome during early life using vancomycin leads to visceral hypersensitivity in rats.59 Conversely, administration of live biotherapeutics, such as Faecalibacterium prausnitzii, Lactobacillus paracasei NCC2461, or Lactobacillus GG, reduces visceral hypersensitivity and intestinal permeability in preclinical models that alter the early-life microbiome.60,61 Unlike in early life, antibiotic administration improves visceral hypersensitivity in adult mice,62 suggesting potential age-dependent effects of the microbiome.

Interestingly, visceral pain responses to colorectal distention vary across the estrous cycle in female mice, but this effect is lost in germ-free animals. Ovariectomy caused visceral hypersensitivity in specific pathogen-free, but not germ-free mice, suggesting an interaction between sex hormones, visceral pain, and the microbiome.63

Building on insights from animal models, human studies exploring fecal microbiome changes in patients with IBS have found specific taxa that positively (Proteobacteria)64 or negatively (Bifidobacterium spp) correlate with the severity of pain.65 Although human microbiome studies have focused largely on the colon, changes in small-intestinal microbial composition, rather than bacterial numbers, appear to differentiate patients with abdominal pain from healthy controls.66 However, the role of small-intestinal microbiota in the pathophysiology of abdominal pain remains unclear. Together, although findings from preclinical models and human studies underscore a role of the gut microbiome, whether these changes are causal to the development of visceral hypersensitivity or a consequence of changes in diet and gastrointestinal motility is unknown.

Gut microbiota-derived metabolites, neurotransmitters, toxins, and cell wall components have emerged as potential factors underlying the pathophysiology of visceral hypersensitivity. These bioactive compounds can (1) sensitize sensory neurons indirectly by stimulating either enteroendocrine cells, which release serotonin, or immune cells, which release chemokines and cytokines, both of which act on distinct neuronal populations, (2) disrupt the intestinal barrier, allowing passage of potentially noxious stimuli, and (3) activate sensory neurons directly, particularly in instances where barrier function is compromised (Figure 2). Most bacteria-derived compounds are pleiotropic, acting via multiple signaling pathways. Thus, they exert wide-ranging effects. Furthermore, gut microbiota can both synthesize and use neurotransmitters, encompassing excitatory, such as glutamate, histamine, dopamine, and norepinephrine, and inhibitory neurotransmitters, such as γ-aminobutyric acid (GABA).67 These neurotransmitters allow intercommunication among microbiota members and the host.

미생물군집과 내장 통증

병리생리학의 진전

장 미생물이 내장 통증 발생에 관여한다는 것은 주로 인간 분변 미생물을 무균 쥐에 이식하거나 쥐 모델에서 생물학적 제제(프로바이오틱스) 또는 항생제, 또는 둘 다를 투여한 후 통증 역치를 측정한 전임상 연구에 기반합니다. 예를 들어, IBS 환자의 분변 미생물로 식민화된 무균 쥐는 직장 확장 자극에 대한 통증 역치가 감소했습니다.57 무균 쥐를 대상으로 한 추가 연구에서는 장 내재 신경세포의 정상적인 흥분성을 유지하는 데 공생 미생물의 역할을 밝혀냈습니다.58

생후 초기 단계에서 반코마이신을 사용하여 장 미생물군집을 교란시키면 쥐에서 내장 과민증이 발생합니다.59 반면, 생물학적 제제(예: Faecalibacterium prausnitzii, Lactobacillus paracasei NCC2461 또는 Lactobacillus GG)를 투여하면 생후 초기 미생물군집을 변화시킨 전임상 모델에서 내장 과민증과 장 투과성이 감소합니다.60,61 초기 생애와 달리 항생제 투여는 성인 쥐의 내장 과민성을 개선합니다.62 이는 미생물군이 연령에 따라 다른 효과를 가질 수 있음을 시사합니다.

흥미롭게도, 암컷 쥐에서 대장 확장 자극에 대한 내장 통증 반응은 발정 주기에 따라 다르지만, 무균 동물에서는 이 효과가 사라집니다. 특정 병원체 무균 쥐에서 난소 적출술은 내장 과민증을 유발했지만, 무균 쥐에서는 그렇지 않았으며, 이는 성 호르몬, 내장 통증, 미생물군집 간의 상호작용을 시사합니다.63

동물 모델에서 얻은 통찰을 바탕으로, IBS 환자의 분변 미생물군 변화에 대한 인간 연구는 통증의 심각성과 긍정적으로 (Proteobacteria)64 또는 부정적으로 (Bifidobacterium spp) 상관관계를 보이는 특정 세균군을 발견했습니다.65 인간 미생물군 연구는 주로 대장에 초점을 맞췄지만, 복통 환자와 건강한 대조군을 구분하는 것은 세균 수보다는 소장 미생물 구성의 변화인 것으로 나타났습니다.66 그러나 소장 미생물군이 복통의 병리생리학에 미치는 역할은 여전히 명확하지 않습니다. 종합적으로, 전임상 모델과 인간 연구의 결과는 장 미생물군의 역할을 강조하지만, 이러한 변화가 내장 과민성의 발병 원인인지, 아니면 식이 변화와 위장관 운동성 변화의 결과인지 여부는 알려지지 않았습니다.

장 미생물군집에서 유래한 대사산물, 신경전달물질, 독소, 세포벽 성분은

내장 과민증의 병리생리학적 기전에 관여하는 잠재적 요인으로 부상했습니다.

이러한 생물활성 화합물은

(1) 세로토닌을 분비하는 장내 내분비 세포나 화학키닌과 사이토카인을 분비하는 면역 세포를 자극하여

      간접적으로 감각 신경 세포를 민감화하거나,

(2) 장 장벽을 손상시켜 잠재적으로 유해한 자극의 통과를 허용하거나,

(3) 특히 장벽 기능이 손상된 경우 감각 신경 세포를 직접 활성화할 수 있습니다(그림 2).

대부분의 세균 유래 화합물은

다중 신호 전달 경로를 통해 작용하는 다기능성 화합물입니다.

따라서 광범위한 효과를 발휘합니다.

또한

장 미생물은 신경전달물질을 합성하고 사용할 수 있으며,

이는 흥분성 신경전달물질(글루타메이트, 히스타민, 도파민, 노르에피네프린)과

억제성 신경전달물질(γ-아미노부티르산(GABA))을 포함합니다.67

이러한 신경전달물질은

미생물군집 구성원 간 및 호스트와의 상호작용을 가능하게 합니다.

Figure viewer

Figure 2 Mechanisms underlying gut microbiome-driven visceral nociception. Gut microbiome-derived products can sensitize peripheral nociceptors directly or act indirectly by stimulating immune cells or enterochromaffin cells, or both, to release cytokines, chemokines, or serotonin, or a combination of these, respectively. The gut microbiome can also modulate intestinal barrier function by altering the luminal bile acid and protease pool or through metabolites such as butyrate. AHR, aryl hydrocarbon receptor; CA, carboxylic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; FFAR, free fatty acid receptor; FXR, farnesoid X receptor; GPR35, G protein-coupled receptor 35; LCA, lithocholic acid; LPS, lipopolysaccharide; LTS, leukotrienes PAMPs, pathogen-associated molecular patterns; PAR2, protease activated receptor 2; PGN, peptidoglycan; TGR5, Takeda G protein-coupled receptor 5; TLR, Toll-like receptor.

그림 2 장 미생물군집에 의한 내장 통각의 메커니즘. 

장 미생물군집에서 유래한 물질은 말초 통각 수용체를 직접적으로 감작시키거나, 면역 세포나 엔테로크로마핀 세포를 자극하여 사이토킨, 케모카인, 세로토닌, 또는 이들의 조합을 분비하도록 간접적으로 작용하거나, 두 가지 방법을 모두 통해 작용할 수 있습니다. 장 미생물군은 장 내 담즙산 및 프로테아제 풀을 변화시키거나 부티레이트와 같은 대사물을 통해 장 장벽 기능을 조절할 수 있습니다. 

AHR, 아릴 하이드로카본 수용체; CA, 카르복시산; CDCA, 케노데옥시콜산; DCA, 데옥시콜산; FFAR, 자유 지방산 수용체; FXR, 파르네소이드 X 수용체; GPR35, G 단백질 결합 수용체 35; LCA, 리토콜산; LPS, 리포폴리사카라이드; LTS, 류코트리엔; PAMPs, 병원체 관련 분자 패턴; PAR2, 프로테아제 활성화 수용체 2; PGN, 펩티도글리칸; TGR5, 다케다 G 단백질 결합 수용체 5; TLR, 톨 유사 수용체.

Enterochromaffin cells are the primary cell type responsible for peripheral serotonin production. They are polymodal chemosensors, capable of detecting specific luminal signals via an array of receptor pathways and translating them to the enteric nervous system by modulating serotonin-sensitive primary afferent nerves.68 Catecholamine neurotransmitters, such as norepinephrine and dopamine, initiate the adrenoceptor alpha 2A (Adrα2A) and the transient receptor potential cation channel subfamily C member 4 (TRPC4) signaling cascade.

On the other hand, short-chain fatty acids (SCFAs) and branched-chain fatty acids, such as isovaleric acid and, to a lesser extent, butyrate, activate the olfactory receptor 558 and P/Q type Cav channel within enterochromaffin cells.68 A multitude of bacterial metabolites, including butyrate, also augment serotonin synthesis within enterochromaffin cells.69 The role played by serotonin in modulating visceral pain, as well as the critical role of enterochromaffin cells in isovalerate-induced visceral hypersensitivity, is discussed further below.

Pathogen-associated molecular pattern molecules, which include bacterial cell wall components such as lipopolysaccharide, bind to pattern recognition receptors such as Toll-like receptors, are present on immune cells and sensory neurons. Pathogen-associated molecular pattern molecules contribute to visceral hypersensitivity by influencing nociceptors directly or by affecting immune cells indirectly, leading to peripheral sensitization.70,71 Diet-derived metabolites from bacterial fermentation, such as SCFAs, indole and indole derivatives, and kynurenine, also modulate visceral nociception. Butyrate exerts antinociceptive effects72 via peroxisome proliferator-activated receptors suppressing the activity of nuclear factor κ-light-chain-enhancer of activated B cells, involved in pain and inflammation.73,74

Butyrate also augments intestinal barrier function via activation of hypoxia inducible factor,75 regulates immune cells via free fatty acid 2/3 receptors,76 and drives epigenetic changes. Tryptophan is converted by microbes to kynurenic acid77 or to indole derivatives,78 both of which exert anti-inflammatory effects via G protein-coupled receptor 35 and aryl hydrocarbon receptor, respectively,79,80

Gut bacteria play an important role in determining the luminal bile acid and protease pool. Bile acid metabolites, including deoxycholic acid, regulate pain through the activation of G protein-coupled bile acid receptor 1, and are present in both primary sensory neurons and macrophages. Proteases contribute to visceral hypersensitivity by targeting intestinal barrier function81 as well as by signaling directly through protease activated receptor 2, present on neurons.82 The luminal protease pool depends on the balance between bacterial proteases83 and suppression of host proteases by bacteria harboring β-glucuronidases.81

The identification of distinct microbiota-driven mechanisms opens the door for novel therapeutic strategies. Currently, microbiota-targeted interventions largely focus on augmenting intestinal barrier function. In preclinical studies, fiber maintained both microbial diversity and barrier function,84 and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) was found to preserve barrier function by decreasing lipopolysaccharide-mediated mast cell activation.85

장크로마핀 세포는

말초 세로토닌 생성을 담당하는 주요 세포 유형입니다.

이 세포는 다중 모드 화학 센서로,

다양한 수용체 경로를 통해 특정 관강 신호를 감지하고

세로토닌에 민감한 구심성 신경의 조절을 통해 장 신경계로 전달합니다.68

카테콜아민 신경전달물질인 노르에피네프린과 도파민은

아드레노수용체 알파 2A (Adrα2A)와

일시적 수용체 잠재력 양이온 채널 하위 가족 C 구성원 4 (TRPC4) 신호 전달 경로를 활성화합니다.

반면,

단쇄 지방산(SCFAs)과 분지쇄 지방산(예: 이소발레릭 산, 상대적으로 적은 양의 부티레이트)은

장크로모핀 세포 내의 후각 수용체 558과 P/Q형 Cav 채널을 활성화합니다.68

부티레이트를 포함한 다양한 세균 대사산물은

장크로모핀 세포 내 세로토닌 합성을 증가시킵니다.69

세로토닌이 내장 통증을 조절하는 역할,

그리고 이소발레이트 유발 내장 과민증에서 엔테로크로마핀 세포의 중요한 역할은

아래에서 자세히 논의됩니다.

병원체 관련 분자 패턴 분자(예: 세균 세포벽 성분인 리포폴리사카라이드)는

면역 세포와 감각 신경에 존재하는

패턴 인식 수용체(예: Toll-like 수용체)에 결합합니다.

병원체 관련 분자 패턴 분자는

통각 수용체를 직접적으로 영향을 주거나

면역 세포를 간접적으로 조절하여

말초 감작을 유발함으로써 내장 과민성에 기여합니다.70,71

세균 발효에서 유래한 대사산물인 SCFAs,

인돌 및 인돌 유도체,

키누레닌은 내장 통각을 조절합니다.

부티레이트는

과산화체 증식 활성화 수용체를 통해 핵 인자 κ-경쇄 증강 인자(NF-κB)의 활성을 억제함으로써

항통각 효과를 발휘합니다.

이 인자는

통증과 염증에 관여합니다.73,74

부티레이트는

저산소 유도 인자(hypoxia inducible factor) 활성화75를 통해

장 장벽 기능을 강화하며,

자유 지방산 2/3 수용체를 통해 면역 세포를 조절76하고,

에피게노믹 변화를 유도합니다.

트립토판은 미생물에 의해 키누레닌산77 또는 인돌 유도체78로 전환되며,

이 두 물질은 각각 G 단백질 결합 수용체 35와 아릴 하이드로카본 수용체를 통해

항염증 효과를 발휘합니다.79,80

장 내 세균은

장 내 담즙산 및 프로테아제 풀의 결정에 중요한 역할을 합니다.

담즙산 대사산물인 데옥시콜산은

G 단백질 결합 담즙산 수용체 1의 활성화를 통해 통증을 조절하며,

이는 일차 감각 신경세포와 대식세포 모두에 존재합니다.

프로테아제는 장 장벽 기능81을 표적으로 삼는 것 외에도

신경세포에 존재하는 프로테아제 활성화 수용체 2를 통해

직접 신호전달을 통해 내장 과민성을 유발합니다.82

장 내 프로테아제 풀은

세균성 프로테아제83와 β-글루쿠로니다제를 보유한 세균에 의해 억제되는

호스트 프로테아제 사이의 균형에 의존합니다.81

미생물군집에 의해 조절되는 독특한 메커니즘의 식별은

새로운 치료 전략의 문을 열었습니다.

현재 미생물군집을 표적으로 한 개입은

주로 장 장벽 기능 강화에 초점을 두고 있습니다.

전임상 연구에서 식이섬유는

미생물 다양성과 장벽 기능을 모두 유지했으며,84

발효성 올리고당, 이당류, 단당류 및 폴리올(FODMAP)이

낮은 식단은 리포폴리사카라이드 매개 마스트 세포 활성화를 감소시켜

장벽 기능을 보존하는 것으로 나타났습니다.85

Clinical trials

There are a multitude of methods to manipulate the microbiome, and thereby microbial metabolites, as a means of treating abdominal pain. SCFA enemas have been studied in IBD, but trials have not reported an effect on abdominal pain.86–88 Fiber has been assessed in IBS, but few trials report abdominal pain outcomes.89,90 One 12-week RCT found there was no benefit of psyllium, a soluble fiber, over placebo,89 but in another trial of psyllium, bran, or placebo, significant improvements in abdominal pain occurred with both psyllium and bran at several time points.90

A network meta-analysis of 12 trials studied the effect of a low FODMAP diet on abdominal pain.91 It was superior to a sham diet but was not superior to standard British Dietetic Association dietary advice for IBS or habitual diet. In contrast, in a RCT comparing a 4-week low FODMAP diet with a sham diet in patients with quiescent IBD with persistent gastrointestinal symptoms, abdominal pain severity and days with abdominal pain did not differ.92 In another 6-week trial of a low FODMAP diet vs normal diet in patients with IBD in remission with ongoing gastrointestinal symptoms, response for abdominal pain frequency, but not severity, was significantly higher with the low FODMAP diet.93 Abdominal pain response rates with rifaximin, a minimally absorbed antibiotic, according to the FDA-recommended end point, were reported in a meta-analysis.56 There was no benefit with rifaximin over placebo.

Although there have been multiple RCTs of fecal microbial transplant (FMT) in both IBS and IBD, summarized in prior meta-analyses,94,95 few report impact of FMT on abdominal pain. Two RCTs of FMT in IBS studied this end point.96,97 One 12-week trial of a single FMT via nasojejunal tube in IBS with predominant bloating reported abdominal pain scores were significantly reduced.96 In the second RCT, 30 mg or 60 mg of a single FMT via gastroscopy led to a significant reduction in abdominal pain at 3 months vs placebo.97 One RCT comparing FMT with usual therapy in active ulcerative colitis reported abdominal pain scores improved significantly with FMT at 2 weeks compared with baseline, but also improved significantly in the usual therapy arm.98

Gelsectan, a prebiotic with mucoprotective and bifidogenic effects, which may reinforce the intestinal barrier, was studied in 1 crossover trial.99 The number of participants with totally to slightly unacceptable abdominal pain was reduced from baseline to 4 weeks compared with placebo. Finally, in a meta-analysis certain combinations of probiotics, Lactobacillus-containing strains, Saccharomyces cerevisiae I-3856, and Bifidobacteria- and Bacillus-containing strains improved abdominal pain, but certainty in the evidence was low to very low across the studies, with heterogeneity between individual trials in most analyses.100

임상 시험

미생물군집을 조작하여 미생물 대사물을 치료 수단으로 활용하는 방법은 다양합니다. SCFA 관장법은 염증성 장 질환(IBD)에서 연구되었지만, 복통에 대한 효과를 보고한 임상 시험은 없습니다.86–88 식이섬유는 과민성 장 증후군(IBS)에서 평가되었지만, 복통 결과에 대한 보고는 드뭅니다.89,90 12주간의 무작위 대조 시험(RCT)에서 수용성 식이섬유인 펙틴이 위약보다 유익하지 않았다는 결과가 나왔습니다.89 그러나 펙틴, 곡물 껍질, 또는 위약을 비교한 다른 시험에서는 펙틴과 곡물 껍질 모두에서 여러 시점에서 복통이 유의미하게 개선되었습니다.90

12건의 임상시험을 분석한 네트워크 메타분석은 저 FODMAP 식이가 복통에 미치는 영향을 연구했습니다.91 이는 가짜 식이요법보다 우수했지만, IBS 또는 습관적 식이에 대한 영국 영양사 협회(British Dietetic Association)의 표준 식이 권고사항보다 우수하지 않았습니다. 반면, 활동성 IBD를 동반한 지속적인 위장관 증상이 있는 환자를 대상으로 4주간의 저 FODMAP 식이와 가짜 식이를 비교한 무작위 대조 시험(RCT)에서 복통의 심각도와 복통 발생 일수는 차이가 없었습니다.92 IBD가 완화되었지만 지속적인 위장관 증상을 보이는 환자에서 저 FODMAP 식이와 일반 식이를 비교한 6주 임상시험에서 복통 빈도에 대한 반응은 저 FODMAP 식이에서 유의미하게 높았지만, 심각도는 차이가 없었습니다.93 FDA가 권장하는 종료점을 기준으로 최소 흡수 항생제인 리파시민의 복통 반응률은 메타분석에서 보고되었습니다.56 리파시민은 위약에 비해 유익한 효과가 없었습니다.

IBS 및 IBD에서 분변 미생물 이식(FMT)에 대한 다수의 무작위 대조 시험(RCT)이 수행되었으며, 이전 메타분석에서 요약되었지만,94,95 FMT가 복통에 미치는 영향을 보고한 연구는 거의 없습니다. IBS에서 FMT를 대상으로 한 두 개의 RCT가 이 종결점을 연구했습니다.96,97 IBS에서 복부 팽만증이 주된 증상인 환자를 대상으로 12주 동안 비위관으로 단일 FMT를 투여한 연구에서 복통 점수가 유의미하게 감소했습니다.96 두 번째 RCT에서 위내시경을 통해 단일 FMT를 30mg 또는 60mg 투여한 결과, 3개월 후 복통이 위약 대비 유의미하게 감소했습니다.97 활동성 궤양성 대장염 환자를 대상으로 FMT와 표준 치료를 비교한 한 RCT에서는 FMT 투여 후 2주 시점에서 복통 점수가 기저치 대비 유의미하게 개선되었지만, 표준 치료군에서도 유의미한 개선이 관찰되었습니다.98

장벽 보호 및 bifidogenic 효과를 가진 프리바이오틱스인 Gelsectan은 1건의 교차 시험에서 연구되었습니다.99 위약 대비 기저치에서 4주 후 완전히 또는 약간 수용 불가능한 복통을 경험한 참가자 수가 감소했습니다. 마지막으로, 메타분석에서 특정 프로바이오틱스 조합(Lactobacillus 함유 균주, Saccharomyces cerevisiae I-3856, Bifidobacteria- 및 Bacillus 함유 균주)이 복통을 개선했지만, 연구 전반에 걸쳐 증거의 확실성은 낮거나 매우 낮았으며, 대부분의 분석에서 개별 시험 간 이질성이 관찰되었습니다.100

Histamine and Visceral Pain

Pharmacology and preclinical studies

Histamine functions as a paracrine signaling molecule that can activate nociceptors in the gastrointestinal tract (Figure 3). It is a member of the biogenic amine family and is synthesized from l-histidine exclusively by l-histidine decarboxylase.101 Histamine signaling to nociceptors in the gut could originate from 2 sources: intestinal tissue or the lumen. In tissue, it is stored in high concentrations, predominantly in mast cells, but also in basophils and eosinophils. However, other cells in the gut also express histidine decarboxylase, including macrophages, neutrophils, platelets, and dendritic cells, and can synthesize and release histamine but do not store it.102 In the lumen of the gastrointestinal tract, there are 3 possible sources: synthesis by microbiota, ingestion of histamine-rich foods, and histamine released from tissues that permeates into the lumen.

히스타민과 내장 통증

약리학 및 전임상 연구

히스타민은

위장관 내의 통각 수용체를 활성화시키는

파라크린 신호 분자로 기능합니다(그림 3).

이는 생물학적 아민 가족에 속하며,

l-히스티딘 디카르복실라아제에 의해

l-히스티딘에서 독점적으로 합성됩니다.101

위장관 내 통각 수용체로의 히스타민 신호 전달은

두 가지 출처에서 비롯될 수 있습니다:

장 조직 또는 장 내강. 조직 내에서는

주로 비만 세포에 고농도로 저장되며,

기저구와 호산구에서도 발견됩니다.

그러나

장 내 다른 세포들도 히스티딘 탈카복실화 효소를 발현하며,

대식세포, 중성구, 혈소판, ден드리틱 세포 등이

히스타민을 합성하고 방출할 수 있지만 저장하지는 않습니다.102

위장관 내강에서는 3가지 가능한 원천이 있습니다:

미생물에 의한 합성,

히스타민이 풍부한 식품의 섭취,

조직에서 방출되어 내강으로 침투하는 히스타민.

Figure viewer

Figure 3 Novel mechanisms causing increased histamine signaling to intestinal nociceptors. (A) This schema shows that after combined food antigen (red triangle) and acute self-limiting colitis or combined food antigen and psychological stress exposure, reexposure to food antigen alone triggers increased IgE release within the intestine (which is not systemic), causing mast cell degranulation within the intestinal wall. The ensuing histamine release causes nociceptor sensitization and increased pain signaling. (B) This schema shows that ingestion of poorly absorbed complex carbohydrates (CHO) (eg, FODMAPs) can stimulate microbial production of histamine. Patients with Klebsiella aerogenes produce up to 100 times more histamine than those lacking this bacterium in their stool samples. Luminal histamine stimulates H4 and H1 receptors, leading to mast cell degranulation with ensuing nociceptor sensitization and increased pain signaling. DRG, dorsal root ganglia.

그림 3 장 내 통각 수용체로의 히스타민 신호 전달 증가를 유발하는 새로운 메커니즘.

(A) 이 도식은 식품 항원(빨간색 삼각형)과 급성 자한성 대장염 또는 식품 항원과 심리적 스트레스 노출이 결합된 후, 식품 항원 단독 재노출이 장 내 IgE 방출 증가(전신적이지 않음)를 유발하여 장 벽 내 비만 세포의 분비체 방출을 초래함을 보여줍니다. 이로 인한 히스타민 방출은 통각 수용체 감작과 통증 신호 전달 증가를 유발합니다.

(B) 이 도식은 흡수율이 낮은 복합 탄수화물(CHO)(예: FODMAPs) 섭취가 미생물 히스타민 생산을 자극할 수 있음을 보여줍니다. Klebsiella aerogenes를 분변 샘플에서 가진 환자는 이 세균이 없는 환자보다 최대 100배 더 많은 히스타민을 생성합니다. 장 내 히스타민은 H4 및 H1 수용체를 자극하여 비만세포의 분비물 방출을 유발하며, 이는 통각 수용체 감작과 통증 신호 증가로 이어집니다. DRG는 후근 신경절을 의미합니다.

Histamine is metabolized by 2 dominant pathways, histamine-N-methyltransferase and diamine oxidase,103 resulting in N-methyl histamine and imidazole acetaldehyde metabolites, respectively. These metabolites also exhibit biological activity (eg, N-methyl histamine), and the preponderance of the pathways may differ between mast cells and microbiota.

Histamine, and possibly some metabolites, can activate 4 GPCRs, H1 to H4.101 These GPCRs signal intracellularly via Gq and cyclic adenosine monophosphate to modulate passive and voltage-gated ion channels on nociceptors and other effector pathways in nonneuronal cells. The distribution of these receptors within the gut suggests histamine activates pain signaling directly through activation of neurons and indirectly via immune cell activation (Figure 3).

In humans,104 H1 receptors are found on connective tissues cells, immune cells, enterocytes, smooth muscle cells, and nerves, H2 receptors are found on gastric parietal cells, enterocytes, immunocytes, enteric nerves, and smooth muscle cells, and H4 receptors are expressed on immune cells, blood vessels, nerves, and enterocytes. H3 receptors have yet to be identified in humans.

Previous studies highlight the role of histamine in patients with IBS, demonstrating increased levels of histamine (and proteases) in mucosal biopsy specimens from patients compared with healthy controls, evidence of mast cell activation, and the ability of histamine in tissue supernatants from patients to exaggerate activation of rodent and human nociceptive neurons.105 Sex differences have not been described. More recent studies show increases in duodenal eosinophils in patients with FD, another source of tissue histamine, implicating a role in abdominal pain in this disorder.106 The triggers resulting in abnormal mast cell-histamine signaling observed in these patients have been unclear, but recent preclinical studies suggest multiple possible etiologies, as outlined below.

When mice develop a self-limiting bacterial colitis and are exposed simultaneously to a food antigen, and then reexposed to the food antigen alone after resolution of infection, they lose oral tolerance to the food antigen.14 This leads to visceral hypersensitivity and mast cell activation with histamine release. This exaggerated pain signaling was blocked by an H1 receptor antagonist, which inhibits histamine signaling to neurons, and by an IgE antibody, which prevents mast cell activation. Tissues exhibited elevated IgE levels, consistent with loss of oral tolerance, but there was no systemic increase in IgE, highlighting immune activation was confined to the intestine.

Injection of common antigens into the rectal mucosa in patients with IBS caused greater wheal and flare responses, compared with healthy volunteers, consistent with the hypothesis that some patients with IBS are sensitized to food antigens.14 Recent preliminary studies suggest psychological stress can also induce loss of oral tolerance to food antigens and lead to mast cell-histamine–mediated visceral hypersensitivity in both the small intestine and colon, a feature observed in many patients with IBS.107

Histamine production by the microbiota may be stimulated by poorly absorbed complex carbohydrates. In a study using germ-free mice to create a humanized IBS mouse model with fecal microbiota from patients with IBS and healthy controls,108 mice given fecal samples from patients with IBS who were high histamine producers, based on stool and urine samples, exhibited visceral hyperalgesia. This exaggerated pain signaling was blocked by H1- and H4- receptor antagonists, suggesting several signaling pathways were involved (Figure 3). Some of the histamine in the luminal samples could originate from the host (eg, mast cell degranulation). However, high histamine producers were found to have microbial species, including Klebsiella aerogenes, in their stool that could make up to 100 times more histamine than those without.

히스타민은 두 가지 주요 대사 경로인 히스타민-N-메틸트랜스퍼레이즈와 다이아민 산화효소에 의해 대사됩니다.103 이 경로는 각각 N-메틸 히스타민과 이미다졸 아세탈데히드 대사물을 생성합니다. 이러한 대사물도 생물학적 활성을 나타내며(예: N-메틸 히스타민), 이 경로의 우세도는 비만 세포와 미생물군집 사이에서 다를 수 있습니다.

히스타민 및 일부 대사산물은 4개의 GPCR(H1~H4)을 활성화할 수 있습니다.101 이 GPCR은 Gq 및 사이클릭 아데노신 모노포스페이트를 통해 세포 내 신호전달을 촉진하여 통각 수용체 및 비신경 세포의 다른 효과기 경로에 있는 수동적 및 전압 의존성 이온 채널을 조절합니다. 이 수용체의 장 내 분포는 히스타민이 신경 세포 활성화로 통증 신호를 직접 활성화하고 면역 세포 활성화로 간접적으로 활성화한다는 것을 시사합니다(그림 3).

인간에서,104 H1 수용체는 결합 조직 세포, 면역 세포, 장 상피 세포, 평활근 세포, 신경에 존재하며, H2 수용체는 위 점막 세포, 장 상피 세포, 면역 세포, 장 신경, 평활근 세포에 존재하며, H4 수용체는 면역 세포, 혈관, 신경, 장 상피 세포에 발현됩니다. H3 수용체는 인간에서 아직 확인되지 않았습니다.

이전 연구들은 IBS 환자의 히스타민 역할을 강조하며, 환자에서 건강한 대조군과 비교해 점막 생검 표본에서 히스타민(및 프로테아제) 수치 증가, 비만세포 활성화 증거, 환자 조직 상청액 내 히스타민이 쥐와 인간 통각 신경 세포의 활성화를 과도하게 유발하는 능력을 보여주었습니다.105 성별 차이는 보고되지 않았습니다. 최근 연구에서는 FD 환자에서 조직 히스타민의 또 다른 원천인 십이지장 에오시노필 증가가 관찰되어 이 질환에서의 복통에 역할을 시사합니다.106 이러한 환자에서 관찰된 비정상적인 마스트 세포-히스타민 신호전달의 유발 요인은 명확하지 않지만, 최근 전임상 연구는 아래에서 설명된 대로 다중 가능한 병인을 제시합니다.

쥐가 자한성 세균성 대장염을 발병한 후 식품 항원에 동시에 노출되고, 감염이 해소된 후 식품 항원 단독에 재노출될 경우, 식품 항원에 대한 구강 내 용인성이 상실됩니다.14 이는 내장 과민성과 히스타민 방출을 동반한 비만세포 활성화를 유발합니다. 이 과도한 통증 신호는 히스타민 신호 전달을 차단하는 H1 수용체 억제제와 비만세포 활성화를 방지하는 IgE 항체에 의해 차단되었습니다. 조직에서는 구강 내 용납 상실과 일치하는 IgE 수치 상승이 관찰되었지만, 전신적인 IgE 증가가 없었으며, 이는 면역 활성화가 장에 국한되었음을 강조합니다.

IBS 환자의 직장 점막에 일반적인 항원을 주입했을 때 건강한 자원자보다 더 큰 부종과 발적 반응이 관찰되었으며, 이는 일부 IBS 환자가 식품 항원에 감작되어 있다는 가설과 일치합니다.14 최근 초기 연구들은 심리적 스트레스가 식품 항원에 대한 구강 내 용납 상실을 유발하고 소장과 대장에서 비만세포-히스타민 매개 내장 과민증을 초래할 수 있음을 제시합니다. 이는 많은 IBS 환자에서 관찰되는 특징입니다.107

미생물군집에 의한 히스타민 생산은 흡수되지 않은 복잡한 탄수화물에 의해 자극될 수 있습니다. IBS 환자와 건강한 대조군의 분변 미생물군을 사용해 인간화 IBS 마우스 모델을 생성한 연구에서,108 분변 및 소변 샘플을 기반으로 히스타민 생성량이 높은 IBS 환자의 분변 샘플을 투여받은 마우스는 내장 과민증을 나타냈습니다. 이 과도한 통증 신호는 H1 및 H4 수용체 차단제로 차단되었으며, 이는 여러 신호 전달 경로가 관여함을 시사합니다 (그림 3). 장 내 샘플의 일부 히스타민은 호스트(예: 비만 세포 분해)에서 유래할 수 있습니다. 그러나 히스타민 생성량이 높은 그룹은 분변에 Klebsiella aerogenes를 포함한 미생물 종을 가지고 있으며, 이는 히스타민 생성량이 없는 그룹보다 최대 100배 더 많은 히스타민을 생성할 수 있습니다.

Clinical trials

Drugs targeting histamine receptors or stabilizing mast cells have not been well studied in gastrointestinal diseases. An 8-week trial of ketotifen, a H1-receptor antagonist, in IBS reported a significant improvement in abdominal pain over placebo.109 Ebastine, another H1-receptor antagonist, has been assessed in IBS.110,111 A 12-week proof-of-concept RCT found rates of relief of abdominal pain were numerically higher with ebastine, but not significantly so. In a subsequent phase IIb placebo-controlled trial, rates of abdominal pain improvement were higher with ebastine, although this was not significant.111 The effect of the mast cell stabilizer disodium cromoglycate on abdominal pain was studied in a RCT in IBS-D.112 In this 6-month study, compared with no treatment, significantly more patients randomized to disodium cromoglycate experienced abdominal pain improvement.

임상 시험

히스타민 수용체를 표적으로 하거나 비만 세포를 안정화시키는 약물은 위장관 질환에서 충분히 연구되지 않았습니다. H1 수용체 차단제인 케토티펜을 사용한 8주 임상 시험에서 IBS 환자의 복통이 위약 대비 유의미하게 개선되었습니다.109 다른 H1 수용체 차단제인 에바스티네는 IBS에서 평가되었습니다.110,111 12주 개념 증명 무작위 대조 시험에서 에바스티네는 복통 완화율이 수치상 더 높았지만 유의미하지 않았습니다. 후속 제2상b 위약 대조 임상시험에서 복통 개선률은 에바스티네에서 더 높았으나, 이는 유의미하지 않았습니다.111 비만세포 안정제 디소디움 크로모글리케이트의 복통에 대한 효과는 IBS-D에서 RCT를 통해 연구되었습니다.112 이 6개월 연구에서, 치료를 받지 않은 그룹에 비해 디소디움 크로모글리케이트를 투여받은 환자의 복통 개선률이 유의미하게 높았습니다.

Transient Receptor Potential Vanilloid 1 and Visceral Pain

Pharmacology and preclinical studies

TRPV1 is a nxxxxonselective ligand-gated cation channel that is highly enriched in gastrointestinal tract nociceptors. It is activated by polymodal stimuli, including mechanical stretch, noxious heat, low pH, exogenous chemical irritants, such as capsaicin (the active ingredient in chili peppers), and endogenous lipid metabolites of arachidonic acid (eg, the endocannabinoid anandamide113). Selective ablation of colon-projecting TRPV1-expressing neurons decreased nociception in response to colorectal distention in mice,22 highlighting its critical role in visceral pain. Estrogens can modulate lumbosacral dorsal root ganglia TRPV1 expression‎, suggesting a potential mechanism for sex differences in visceral pain.114

Sensitization of TRPV1 by inflammatory mediators, such as histamine,110 is one of the key pathways in mediating peripheral visceral hypersensitivity, as discussed above. However, TRPV1 expression‎ does not necessarily correlate with receptor sensitization. For example, in patients with IBS who were hypersensitive to rectal distention, rectal application of capsaicin caused increased pain perception. No change in TRPV1 expression‎ was noted when comparing hypersensitive and normosensitive patients with IBS, suggesting that although TRPV1 expression‎ is important, additional factors, such as receptor sensitization or central factors, or both, are necessary in mediating visceral pain.115

Although most of the studies have focused on TRPV1 sensitization in IBS and FD,113 TRPV1 may also play a role in chronic visceral pain in patients with IBD in remission. Rectal TRPV1 expression‎ was increased in patients with IBD in endoscopic remission with chronic visceral pain and correlated with patient-reported symptoms.116 Visceral hyperalgesia was TRPV1-dependent in postinflammatory mice,117 and they also displayed increased SCFA-producing microbiota and stool SCFA content. These microbial-derived SCFAs increased capsaicin-evoked calcium responses in the postinflammatory state, suggesting that microbial metabolites can sensitize TRPV1.118

일시적 수용체 잠재력 반일리노이드 1(TRPV1)과 내장 통증:

약리학 및 전임상 연구

TRPV1은 위장관 통각 수용체에 풍부하게 존재하는 비선택적 리간드 의존성 양이온 채널입니다. 이 채널은 기계적 스트레치, 유해 열, 저 pH, 캡사이신(고추의 활성 성분)과 같은 외인성 화학 자극제, 아라키돈산 대사산물(예: 내인성 대마초 유사 물질 아난다미드113) 등에 의해 활성화됩니다. 대장 투사 TRPV1 발현 신경세포의 선택적 제거는 쥐에서 대장 확장 자극에 대한 통각 감소를 유발했으며,22 이는 내장 통증에서의 TRPV1의 핵심 역할을 강조합니다. 에스트로겐은 요추-천추 후근 신경절 TRPV1 발현을 조절할 수 있으며, 이는 내장 통증의 성별 차이에 대한 잠재적 메커니즘을 시사합니다.114

염증 매개체(예: 히스타민)에 의한 TRPV1의 감작은 위에서 논의된 바와 같이 말초 내장 과민성의 매개 경로 중 하나입니다. 그러나 TRPV1 발현은 수용체 감작과 반드시 상관관계가 없습니다. 예를 들어, 직장 확장 자극에 과민반응을 보이는 IBS 환자에게 캡사이신을 직장 적용했을 때 통증 인식이 증가했습니다. IBS 환자의 과민반응군과 정상반응군을 비교했을 때 TRPV1 발현에 변화가 관찰되지 않았으며, 이는 TRPV1 발현이 중요하지만 수용체 감작이나 중추적 요인, 또는 둘 다의 추가 요인이 내장 통증 매개에 필요함을 시사합니다.115

대부분의 연구는 IBS와 FD에서의 TRPV1 감작에 초점을 맞췄지만,113 TRPV1은 IBD 완화기 환자의 만성 내장 통증에도 역할을 할 수 있습니다. 내시경적 완화 상태에 있는 IBD 환자 중 만성 내장 통증을 보이는 환자에서 직장 TRPV1 발현이 증가했으며, 이는 환자 보고 증상과 상관관계를 보였습니다.116 염증 후 마우스에서 내장 과민증은 TRPV1에 의존적이었으며,117 이들은 또한 SCFA 생성 미생물군과 대변 SCFA 함량이 증가했습니다. 이러한 미생물 유래 SCFA는 염증 후 상태에서 캡사이신 유발 칼슘 반응을 증가시켜 미생물 대사산물이 TRPV1을 감작시킬 수 있음을 시사합니다.118

Clinical trials

Peppermint oil, as well as being a smooth muscle relaxant, may have effects on TRPV1 signaling. A meta-analysis showed it was more efficacious than placebo for abdominal pain.119 However, benefit was modest, with heterogeneity between studies, and most trials did not use FDA-recommended end points. Although capsaicin stimulates the TRPV1 receptor, leading to worsening abdominal pain, repeated administration down-regulates the receptor. A 6-week trial in IBS showed abdominal pain scores were significantly lower, compared with baseline, in patients receiving red pepper pills compared with those receiving placebo.120 A similar 5-week study in FD demonstrated a significant reduction in epigastric pain scores with red pepper vs placebo.121 However, patients in both trials randomized to red pepper dropped out due to pain exacerbations.

임상 시험

페퍼민트 오일은 평활근 이완제 역할을 하며 TRPV1 신호전달에 영향을 미칠 수 있습니다. 메타분석 결과 복통에 대해 위약보다 더 효과적이었지만, 효과는 미미했으며 연구 간 이질성이 있었고 대부분의 연구는 FDA 권장 종료점을 사용하지 않았습니다. 캡사이신은 TRPV1 수용체를 자극해 복통을 악화시키지만, 반복 투여 시 수용체를 하향 조절합니다. IBS 환자를 대상으로 한 6주 임상 시험에서, 고추 알약을 복용한 환자의 복통 점수는 위약 그룹에 비해 기저치 대비 유의미하게 낮았습니다.120 FD 환자를 대상으로 한 유사한 5주 연구에서도 고추 대비 위약 그룹에서 상복부 통증 점수가 유의미하게 감소했습니다.121 그러나 두 임상 시험에서 고추 그룹에 무작위 배정된 환자들은 통증 악화로 인해 연구를 중도 탈퇴했습니다.

Serotonin (5-Hydroxytryptamine) and Visceral Pain

Pharmacology and preclinical studies

The monoamine neurotransmitter 5-hydroxytryptamine (5HT) plays an integral role in initiation of intrinsic gut reflexes regulating motility, secretion, and vasodilation. It also participates in the pathogenesis of visceral pain via afferent nerve 5-HT3 and 5-HT4 receptors; drugs that modulate these receptors have been used extensively in the treatment of visceral hypersensitivity.122 The actions of 5HT are terminated by the serotonin selective reuptake transporter, a peripheral target of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and serotonin norepinephrine reuptake inhibitors122 (SNRIs).

Genetic polymorphisms in the 5-HT3 receptor and the serotonergic synthetic enzyme, tryptophan hydroxylase, are associated with increased IBS susceptibility, whereas SSRI transporter polymorphisms are associated with both IBS and FD.123 Multiple studies report changes in 5HT synthesis, reuptake, and release in IBS,124 suggesting dysregulated 5HT signaling contributes to the pathophysiology of visceral pain. Surprisingly, few studies eval‎uating the role of TCAs in visceral pain have been performed in rodent models.

Although 5HT can be secreted by enteric neurons and mucosal mast cells, most of the body’s 5HT is synthesized and stored by enterochromaffin cells.122 Enterochromaffin cells are electrically excitable, and display axon-like basal processes, forming functional connections with extrinsic and intrinsic afferent neurons, termed neuropods.68,125 Enterochromaffin cells function as luminal sensory transducers, releasing 5HT in response to dietary nutrients and microbial products, as well as mucosal distortion via mechanosensitive Piezo-02 channels.126 5HT release by enterochromaffin cells, thus initiates intrinsic gut reflexes and stimulates extrinsic nerves.

A recent study eval‎uated the role of a mucosal afferent-enterochromaffin cell circuit in the pathogenesis of visceral hypersensitivity using transgenic mice,26 where enterochromaffin cells could be activated or silenced selectively. Direct activation of enterochromaffin cells elicited 5HT release and was sufficient to cause both acute and chronic visceral hypersensitivity to colorectal distention. Remarkably, activation of enterochromaffin cells was sufficient to elicit anxiety-like behavior in mice. These effects were inhibited by the 5HT3 antagonist alosetron, which decreased mucosal afferent activity. Conversely, silencing activity of enterochromaffin cells attenuated 5HT release and visceral hypersensitivity mediated by the microbial metabolite, isovalerate, in male mice. The mucosal afferent-enterochromaffin cell circuit demonstrated high tonic activity in female, but not male, mice suggesting a sex-specific contribution to pain signaling. Together, these data demonstrate that the enterochromaffin cell-mucosal afferent circuit plays an essential role in pathogenesis of visceral hypersensitivity.26

It is possible that the GC-C pathway also regulates 5HT secretion from enterochromaffin cells. GC-C is expressed not only by enterocytes but also by a subtype of monoamine synthesis-expressing neuropods enriched in the proximal intestine of mice.36 GC-C enriched neuropods formed functional connections with nociceptors in cocultures and caused spontaneous nociceptor activation, which was abolished by linaclotide. The antinociceptive effects of linaclotide on the response to colorectal distention were lost in mice that were deficient in neuropod GC-C.36 Thus, it is possible that enterochromaffin GC-C activation regulates 5HT tone, but whether this mechanism is active in vivo is unclear.

세로토닌 (5-하이드록시트립토판)과 내장 통증

약리학 및 전임상 연구

모노아민 신경 전달 물질인 5-하이드록시트립타민(5HT)은 운동, 분비 및 혈관 확장을 조절하는 내인성 장 반사의 개시에 필수적인 역할을 합니다. 또한 구심성 신경 5-HT3 및 5-HT4 수용체를 통해 내장 통증의 발병에도 관여하며, 이러한 수용체를 조절하는 약물은 내장 과민증의 치료에 광범위하게 사용되어 왔습니다.122 5HT의 작용은 세로토닌 선택적 재흡수 운반체에 의해 종결되며, 이는 선택적 세로토닌 재흡수 억제제(SSRIs), 삼환계 항우울제(TCAs), 세로토닌 노르에피네프린 재흡수 억제제(SNRIs)의 말초 표적입니다.

5-HT3 수용체와 세로토닌 합성 효소인 트립토판 하이드록시라제의 유전적 다형성은 IBS 취약성과 연관되어 있으며, SSRI 운반체 다형성은 IBS와 FD 모두와 연관되어 있습니다.123 여러 연구에서 IBS에서 5HT 합성, 재흡수, 방출의 변화가 보고되었으며,124 이는 조절 장애된 5HT 신호전달이 내장 통증의 병리생리학에 기여한다는 것을 시사합니다. 놀랍게도, 쥐 모델에서 TCAs의 내장 통증 역할 평가 연구는 거의 수행되지 않았습니다.

5HT는 장 신경 세포와 점막 비만 세포에 의해 분비될 수 있지만, 체내의 5HT 대부분은 장 크로마핀 세포에 의해 합성 및 저장됩니다.122 장 크로마핀 세포는 전기적으로 흥분성이 있으며, 축삭과 유사한 기저 과정을 나타내며, 신경포드라고 하는 외인성 및 내인성 구심성 신경 세포와 기능적 연결을 형성합니다.68,125 엔테로크로마핀 세포는 루멘 감각 변환기로 기능하며, 식이 영양소 및 미생물 제품에 반응하여 5HT를 분비하며, 기계감각성 Piezo-02 채널을 통해 점막 변형에도 반응합니다.126 엔테로크로마핀 세포의 5HT 분비는 내인성 장 반사를 유발하고 외인성 신경계를 자극합니다.

최근의 연구에서는, 장크로마핀 세포를 선택적으로 활성화하거나 침묵시킬 수 있는 형질전환 마우스를 사용하여, 내장 과민증의 발병 기전에서 점막 구심성-장크로마핀 세포 회로의 역할을 평가했습니다26. 장크로마핀 세포를 직접 활성화하면 5HT가 방출되어, 대장 팽창에 대한 급성 및 만성 내장 과민증을 유발하기에 충분했습니다. 놀랍게도, 장크로마핀 세포의 활성화는 쥐에서 불안과 유사한 행동을 유발하기에 충분했습니다. 이러한 효과는 점막 구심성 활동을 감소시키는 5HT3 길항제 알로세트론에 의해 억제되었습니다. 반대로, 장크로마핀 세포의 활동을 억제하면 수컷 쥐에서 미생물 대사 산물인 이소발레레이트에 의해 매개되는 5HT 방출과 내장 과민성이 약화되었습니다. 점막 구심성-엔테로크로마핀 세포 회로는 암컷 쥐에서 높은 강장 활성을 보였지만 수컷 쥐에서는 나타나지 않았는데, 이는 통증 신호 전달에 성별에 따른 차이가 있음을 시사합니다. 이 모든 데이터를 종합하면, 엔테로크로마핀 세포-점막 구심성 회로가 내장 과민증의 발병에 중요한 역할을 한다는 것이 증명됩니다.26

GC-C 경로가 엔테로크로마핀 세포로부터의 5HT 분비도 조절할 수 있습니다. GC-C는 장 상피세포뿐만 아니라 쥐의 근위 장에 풍부하게 존재하는 모노아민 합성 발현 신경포드(neuropod)의 하위 유형에서도 발현됩니다.36 GC-C가 풍부한 신경포드는 공배양에서 통각 수용체와 기능적 연결을 형성했으며, 이는 linaclotide에 의해 소실되었습니다. 린악로티드의 대장 확장 자극에 대한 항통각 효과는 신경포드 GC-C 결핍 마우스에서 소실되었습니다.36 따라서 엔테로크로마핀 GC-C 활성화가 5HT 토너를 조절할 수 있지만, 이 메커니즘이 체내에서 활성화되는지는 명확하지 않습니다.

Clinical trials

The efficacy of the 5HT3-receptor antagonists alosetron and ramosetron, according to the FDA-recommended end point for abdominal pain, has been reported in multiple trials in IBS-D, pooled in a meta-analysis.56 Ramosetron, 2.5 μg daily and 5 μm daily, and alosetron, 1 mg twice daily, were superior to placebo, although alosetron has been associated with ischemic colitis. Varying doses of ondansetron, another 5HT3-receptor antagonist with a long history of safety, were assessed in 3 trials in IBS-D, summarized in another meta-analysis.127 The drug was not superior to placebo for pain.

For 5HT4-receptor agonists, in a pooled analysis of data from 4 RCTs in IBS, tegaserod, 6 mg twice daily, was more efficacious for pain than placebo.128 In two 6-week trials of tegaserod in FD, 6 mg twice daily was superior to placebo for abdominal pain in 1 RCT but not the other.129 Safety issues arising from cardiovascular and cerebrovascular ischemic events led to the withdrawal of tegaserod. Although it was reintroduced briefly, tegaserod is now no longer available. Prucalopride was assessed in chronic constipation and was efficacious,130 but no RCTs report its efficacy in improving abdominal pain, and it has never been tested in IBS or FD.

Although SSRIs, TCAs, and SNRIs are antidepressants, in the context of treating abdominal pain, they act as gut-brain neuromodulators involving, at least in part, 5-HT131; discussion of the central actions of these compounds is beyond the scope of this review. SSRIs have been assessed in IBS and FD, with no impact on abdominal pain in IBS in a prior meta-analysis,132 and a reduction in pain scores in FD in a single RCT of escitalopram, 10 mg once daily, but with no benefit over placebo.133 TCAs, however, were more efficacious than placebo for abdominal pain in IBS in a meta-analysis of 4 RCTs132 and more recently in a 6-month trial in 463 patients.134 In one 12-week trial in refractory FD, imipramine led to a significant reduction in epigastric pain scores vs placebo,135 but another trial of amitriptyline demonstrated no benefit.133 The SNRI venlafaxine was assessed in a single 12-week RCT in IBS; abdominal pain frequency scores were reduced significantly compared with placebo.136 An RCT of FD did not report its effect on abdominal pain.137

임상 시험

FDA가 권장하는 복통 평가 지표를 기준으로 5HT3 수용체 길항제 알로세트론과 라모세트론의 효능은 IBS-D 환자 대상 다수 임상시험에서 보고되었으며, 메타분석에서 통합되었습니다.56 라모세트론 2.5 μg/일 및 5 μm/일, 알로세트론 1 mg 2회/일은 위약보다 우월했으나, 알로세트론은 허혈성 대장염과 연관되었습니다. 5HT3 수용체 길항제 중 안전성 기록이 긴 온다세트론의 다양한 용량은 IBS-D 환자 대상 3건의 임상시험에서 평가되었으며, 다른 메타분석에서 요약되었습니다.127 이 약물은 통증 완화에서 위약보다 우월하지 않았습니다.

5HT4 수용체 작용제인 테가세로드는 IBS 환자 대상 4건의 무작위 대조 시험(RCT) 데이터 통합 분석에서 통증 완화 효과에서 위약보다 우수했습니다.128 FD 환자 대상 6주 임상 시험 2건에서 테가세로드 6mg 하루 2회 투여는 1건의 RCT에서 복통 완화에서 위약보다 우수했으나 다른 시험에서는 그렇지 않았습니다.129 심혈관 및 뇌혈관 허혈성 사건으로 인한 안전성 문제로 인해 tegaserod는 시판이 중단되었습니다. 일시적으로 재 도입되었지만, 현재는 더 이상 사용되지 않습니다. Prucalopride는 만성 변비에서 유효성이 입증되었지만,130 복통 개선에 대한 RCT 보고는 없으며, IBS 또는 FD에서 테스트된 적이 없습니다.

SSRIs, TCAs, 및 SNRIs는 항우울제이지만, 복통 치료 맥락에서는 5-HT를 통해 장-뇌 신경 조절 작용을 부분적으로 포함하여 작용합니다.131 이 화합물의 중추 신경계 작용에 대한 논의는 본 검토의 범위를 넘어섭니다. SSRIs는 IBS와 FD에서 평가되었으며, 이전 메타분석에서 IBS의 복통에 영향을 미치지 않았으며,132 FD에서 에스시탈로프람 10mg 하루 1회 투여 시 단일 RCT에서 통증 점수가 감소했지만 위약 대비 유의미한 차이는 없었습니다.133 TCAs는 4건의 RCT 메타분석에서 IBS의 복통에 대해 위약보다 유효했으며, 최근 463명을 대상으로 한 6개월 임상시험에서도 유사한 결과가 보고되었습니다.134 난치성 FD 환자 대상 12주 임상시험에서 이미프라민은 위통 점수에서 위약 대비 유의미한 감소 효과를 보였으나,135 아미트립틸린을 평가한 다른 임상시험에서는 유익성이 확인되지 않았습니다.133 SNRI인 벤라팍신은 IBS 환자 대상 단일 12주 RCT에서 평가되었으며, 복통 빈도 점수가 위약 대비 유의미하게 감소했습니다.136 FD 환자 대상 RCT에서는 복통에 대한 효과가 보고되지 않았습니다.137

Cannabinoids and Visceral Pain

Pharmacology and preclinical studies

Cannabinoids are widely used alternative therapies to treat abdominal pain in both IBD and IBS.138,139 The actions of cannabinoids are mediated via the endocannabinoid system, which regulates gastrointestinal motility, secretion, immune function, intestinal permeability, and visceral hypersensitivity.140

The classical components of the endocannabinoid system are the endogenous cannabinoid ligands, anandamide, and 2-arachidonoylglycerol, as well as their biosynthetic and degradative enzymes. These are found throughout the microbiota-gut-brain axis, including the epithelium, enterochromaffin cells, enteric nervous system, and immune system, as well as extrinsic afferent nerves, where they primarily exert an antinociceptive effect. Anandamide is also an agonist at TRPV1. Thus, endocannabinoids have both pronociceptive and antinociceptive effects, depending on the receptor.140 Interestingly, commensal bacteria can produce endocannabinoid-like molecules,141 although whether a microbial source of endocannabinoid-like molecules plays a role in visceral hypersensitivity is unknown.

In animal models of stress-induced visceral hypersensitivity and in postinflammatory models, CB1 and CB2 agonists decrease the visceromotor response to colorectal distention.140,142–144 Endocannabinoids can either exert their antinociceptive actions directly via CB1 and CB2 receptors expressed on nociceptors142,145 or indirectly via down-regulation of mast cell or macrophage activation.140 However, clinical use of cannabinoids is hampered by psychotropic adverse effects. Accordingly, there has been interest in synthesizing peripherally restricted cannabinoid receptor agonists.142–144

A recent preclinical study of the peripherally restricted CB2 receptor agonist, olorinab, was performed in rodent models of acute colitis and postinflammatory visceral pain.142 Olorinab reversed the colitis-induced hypersensitivity to colorectal distention in both the acute and postinflammatory state; no effects on visceral pain were seen when olorinab was given to controls. Olorinab was able to decrease mechanosensitivity of ex vivo afferent nerves in a dose-dependent manner, both in acute colitis and in the postinflammatory state, although CB2 expression‎ was not up-regulated in afferent nerves compared with controls.142 Unfortunately, only male mice were eval‎uated in this study, although CB2 expression‎ is increased in female patients with IBS.146 These data suggest CB2 receptors on visceral afferents are sensitized by inflammation and, in turn, play a regulatory anti-nociceptive role.

Clinical trials

In a 12-week phase II dose-ranging study of olorinab in IBS, the proportion of patients experiencing improvement in abdominal pain was not significantly higher with any dose studied.147 However, in those with moderate to severe pain at baseline, abdominal pain scores were significantly improved with 50 mg 3 times daily. No placebo-controlled trials of this drug in IBD have been conducted, although an 8-week open-label randomized study recruiting patients with Crohn’s disease who reported abdominal pain found a significant reduction in pain scores from baseline with olorinab.148 There is no evidence for other drugs acting on cannabinoid receptors for treating abdominal pain in gastrointestinal disorders.149

칸나비노이드와 내장 통증

약리학 및 전임상 연구

대마초는 IBD와 IBS에서 복통 치료를 위한 대체 요법으로 널리 사용됩니다.138,139 대마초의 작용은 위장 운동, 분비, 면역 기능, 장 투과성, 내장 과민성을 조절하는 내인성 대마초 시스템(endocannabinoid system)을 통해 매개됩니다.140

내인성 대마초 수용체 시스템의 주요 구성 요소는 내인성 대마초 리간드인 아난다미드와 2-아라키도노일글리세롤, 그리고 이들의 생합성 및 분해 효소입니다. 이들은 상피, 장 크로마핀 세포, 장 신경계, 면역계 등 미생물군-장-뇌 축 전체에서 발견되며, 주로 항통각 작용을 하는 외인성 구심성 신경에서도 발견됩니다. 아난다미드는 TRPV1 수용체의 작용제입니다. 따라서 내인성 대마초 성분은 수용체에 따라 통증 촉진 효과와 통증 억제 효과를 모두 가집니다.140 흥미롭게도 공생 세균은 내인성 대마초 유사 분자를 생성할 수 있지만, 미생물 기원 내인성 대마초 유사 분자가 내장 과민성에 역할을 하는지는 알려지지 않았습니다.

스트레스 유발 내장 과민증 동물 모델과 염증 후 모델에서 CB1 및 CB2 작용제는 대장 확장 시 내장 운동 반응을 감소시킵니다.140,142–144 내인성 대마초 유사 물질은 통각 수용체에 발현된 CB1 및 CB2 수용체를 통해 직접적으로 항통각 작용을 발휘하거나,142,145 비만 세포 또는 대식세포 활성화를 억제하는 간접적인 경로를 통해 작용할 수 있습니다.140 그러나 대마초 유사 물질의 임상적 사용은 정신적 부작용으로 인해 제한됩니다. 이에 따라 말초 제한적 대마초 수용체 작용제의 합성에 대한 관심이 높아졌습니다.142–144

최근 말초 제한적 CB2 수용체 작용제인 올로리나브(olorinab)의 전임상 연구가 급성 대장염 및 염증 후 내장 통증 동물 모델에서 수행되었습니다.142 올로리나브는 급성 및 염증 후 상태에서 대장 확장 유발 과민성을 역전시켰으며, 대조군에 올로리나브를 투여했을 때는 내장 통증에 대한 효과가 관찰되지 않았습니다. 올로리나브는 급성 대장염 및 염증 후 상태 모두에서 용량에 따라 생체 외 구심성 신경의 기계 민감성을 감소시킬 수 있었지만, 대조군에 비해 구심성 신경에서 CB2 발현이 증가하지는 않았습니다.142 불행히도, 이 연구에서는 수컷 마우스만 평가되었지만, IBS 여성 환자에서는 CB2 발현이 증가합니다.146 이러한 데이터는 내장 구심성 신경의 CB2 수용체가 염증에 의해 민감해지며, 그 결과 항통각 조절 역할을 한다는 것을 시사합니다.

임상 시험

IBS 환자를 대상으로 한 12주 제2상 용량 탐색 연구에서 olorinab 투여 시 복통 개선을 경험한 환자의 비율은 어떤 용량에서도 유의미하게 높지 않았습니다.147 그러나 기저치에서 중등도에서 중증의 통증을 가진 환자에서 50mg 3회 투여 시 복통 점수가 유의미하게 개선되었습니다. 이 약물의 IBD에 대한 위약 대조 임상 시험은 수행되지 않았으나, 크론병 환자로 복통을 호소한 환자를 대상으로 한 8주간의 개방형 무작위 연구에서 olorinab 투여 시 기저치 대비 통증 점수가 유의미하게 감소했습니다.148 위장관 장애로 인한 복통 치료를 위해 대마초 수용체에 작용하는 다른 약물에 대한 증거는 없습니다.149

γ-Aminobutyric Acid and Visceral Pain

Pharmacology and preclinical studies

Functional GABA receptors have been identified in the nerve terminals of colonic afferents. The activation of GABA receptors (GABAA and GABAB) by endogenous GABA decreases sensitivity of colonic afferents, whereas GABAA activation also reduces visceral pain perception.150 Functional GABAergic transmission has also been found in nociceptors, producing strong analgesic effects.151 In addition to endogenous production, certain bacteria expressing glutamate decarboxylase, can produce GABA from glutamate.67 In rodent models, GABA-producing bacteria have an analgesic effect in stress-induced152 and fecal-retention153 models of visceral hypersensitivity.

Clinical trials

There has been 1 RCT of pregabalin in both FD and IBS, but no trials in other painful gastrointestinal disorders and no trials of gabapentin. Abdominal pain scores were significantly lower in patients assigned to titrated pregabalin vs placebo in a 12-week trial in IBS.154 Similarly, pregabalin, 75 mg daily, was superior to placebo for epigastric pain scores in an 8-week trial in FD.155

Conclusions

Chronic visceral pain represents a substantial burden to patients. Despite the potential for the evidence-based treatments described above, a need remains for the development of novel therapeutics to treat sensitization of peripheral pain pathways effectively. Future directions should include the identification of microbial vs host sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), similar to current work eval‎uating histamine (Figure 4).

γ-아미노부티르산(GABA)과 내장 통증

약리학 및 전임상 연구

기능성 GABA 수용체는 결장 구심성 신경 말단에서 확인되었습니다. 내인성 GABA에 의한 GABA 수용체(GABAA 및 GABAB)의 활성화는 결장 구심성 신경의 민감도를 감소시키는 반면, GABAA의 활성화는 내장 통증의 지각도 감소시킵니다.150 기능적 GABAergic 전달은 통각 수용체에서도 발견되었으며, 강력한 진통 효과를 유발합니다.151 내인성 생산 외에도 글루타메이트 탈카복실화 효소를 발현하는 특정 세균은 글루타메이트로부터 GABA를 생성할 수 있습니다.67 쥐 모델에서 GABA 생성 세균은 스트레스 유발성152 및 변비 유발성153 내장 과민증 모델에서 진통 효과를 나타냅니다.

임상 시험

FD와 IBS에서 프레가발린에 대한 1건의 무작위 대조 시험(RCT)이 진행되었지만, 다른 통증성 위장관 장애에 대한 시험이나 가바펜틴에 대한 시험은 없습니다. IBS 환자에서 12주 임상 시험에서 용량을 조절된 프레가발린을 투여받은 환자의 복통 점수가 위약 대비 유의미하게 낮았습니다.154 마찬가지로, FD 환자에서 8주 임상 시험에서 하루 75mg의 프레가발린이 상복부 통증 점수에서 위약보다 우수했습니다.155

결론

만성 내장 통증은 환자에게 심각한 부담을 초래합니다. 위에서 설명된 근거 기반 치료법의 잠재적 효과에도 불구하고, 말초 통증 경로의 감작을 효과적으로 치료하기 위한 새로운 치료법 개발이 필요합니다. 향후 연구 방향에는 미생물 vs 호스트 소스의 말초 표적(예: GABA, 내인성 대마초 유사 물질, 5HT)을 식별하는 것이 포함되어야 하며, 이는 현재 히스타민을 평가하는 연구(그림 4)와 유사합니다.

Figure viewer

Figure 4 Areas for future investigation in peripheral mechanisms of visceral pain. There is a need to identify peripheral mechanisms underlying visceral pain and develop novel therapeutic agents to treat patients. Identification of microbial vs host sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), is one such mechanistic area. Eval‎uation of the relative contribution of each pathophysiologic mechanism to nociceptor sensitization in individual patients, and thus use of combination therapies targeting these mechanisms, is key. For opiates, some promising strategies for the development of safe yet effective opiate therapies are the development of pH-sensitive opiate analogues active at the site of inflammation, use of peripherally restricted agents or subthreshold combinations of opiates, and CB1 receptor agonists. Because chronic visceral pain is more common in women, future studies should eval‎uate whether pain mechanisms are sex-specific and whether treatments should be used in a sex-specific manner. ♀, female; ♂, male.

With respect to the microbiome, research should avoid observational-based community profiling and focus on mechanistic approaches eval‎uating how microbiota or microbial products, or both, interact with nociceptors. Methods to test the relative contribution of each pathophysiologic mechanism to the sensitization of peripheral nociceptors and their role in overlapping pain syndromes in individual patients is also required. This would allow the use of specific drug combinations to target multiple mechanisms synergistically.

Given the sex bias of chronic visceral pain, future studies should eval‎uate whether pain mechanisms are sex-specific or whether treatments should be used in a sex-specific manner. Identifying whether differing or similar peripheral mechanisms are involved in the development of chronic visceral pain in patients with IBD vs painful DGBI will be important. Finally, eval‎uation of the relative contribution of peripheral vs central sensitization to symptoms would be important to individualize patient therapy. Continued multidisciplinary collaboration between clinician-scientists and bench-based scientists with the use of innovative reverse translational approaches is necessary to advance this field, identify new target pathways, and improve the clinical management of patients.

그림 4 내장 통증의 주변 메커니즘에 대한 미래 연구 분야. 내장 통증의 기반이 되는 주변 메커니즘을 규명하고 환자를 치료하기 위한 새로운 치료제를 개발하는 것이 필요합니다. 미생물과 호스트의 주변 표적(예: GABA, 내인성 대마초 유사 물질, 5HT)의 출처를 구분하는 것은 이러한 메커니즘 연구의 한 분야입니다. 개별 환자에서 각 병리생리학적 메커니즘이 통각 수용체 감작화에 미치는 상대적 기여도를 평가하고, 이를 표적으로 하는 조합 요법을 사용하는 것이 핵심입니다. 아편제제의 경우, 염증 부위에서 활성되는 pH 감응성 아편 유사체 개발, 말초 제한적 제제 또는 아편제의 임계치 이하 조합 사용, CB1 수용체 작용제 등이 안전하면서도 효과적인 아편제 치료제 개발을 위한 유망한 전략입니다. 만성 내장 통증은 여성에서 더 흔하기 때문에, 향후 연구에서는 통증 메커니즘이 성별 특이적인지, 그리고 치료법이 성별에 따라 적용되어야 하는지 평가해야 합니다. ♀, 여성; ♂, 남성.

미생물군집과 관련하여, 관찰 기반 커뮤니티 프로파일링을 피하고 미생물군집이나 미생물 제품, 또는 둘 다와 통각 수용체 간의 상호작용을 평가하는 기전적 접근법에 초점을 맞춰야 합니다. 개별 환자의 말초 통각 수용체 감작화에 각 병리생리학적 기전의 상대적 기여도를 평가하고, 중복되는 통증 증후군에서의 역할을 규명하는 방법도 필요합니다. 이는 다중 기전을 시너지적으로 표적화하는 특정 약물 조합의 사용을 가능하게 할 것입니다.

만성 내장 통증의 성별 편향을 고려할 때, 향후 연구는 통증 메커니즘이 성별 특이적인지, 또는 치료가 성별 특이적으로 적용되어야 하는지 평가해야 합니다. IBD 환자와 통증성 DGBI 환자에서 만성 내장 통증의 발병에 관여하는 주변 메커니즘이 서로 다를지 또는 유사한지 확인하는 것이 중요합니다. 마지막으로, 증상에 대한 주변 감작과 중추 감작의 상대적 기여도를 평가하는 것은 환자 치료를 개인화하는 데 중요합니다. 임상 과학자와 기초 연구자 간의 지속적인 다학제적 협력을 통해 혁신적인 역전 번역 접근법을 활용하는 것이 이 분야를 발전시키고 새로운 표적 경로를 식별하며 환자의 임상 관리를 개선하는 데 필수적입니다.

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Reviews in Basic and Clinical Gastroenterology and HepatologyVolume 166, Issue 6p976-994June 2024Open access

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Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments

Alexander C. Ford1,2,∗ ∙ Stephen Vanner3,∗ ∙ Purna C. Kashyap4 ∙ Yasmin Nasser5 ynasser@ucalgary.ca

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Abstract

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

Keywords

1. Visceral Pain
2. Inflammatory Bowel Disease
3. Irritable Bowel Syndrome
4. Histamine
5. Serotonin
6. Microbiome
7. Abdominal Pain
8. Inflammation

Abbreviations used in this paper

1. HT (5-hydroxytryptamine)
2. CB1 (cannabinoid receptor 1)
3. cGMP (guanosine 3′,5′-cyclic monophosphate)
4. DGBI (disorders of gut-brain interaction)
5. DOR (δ-opioid receptor)
6. FD (functional dyspepsia)
7. FDA (Food and Drug Administration)
8. FMT (fecal microbial transplant)
9. FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols)
10. GABA (γ-aminobutyric acid)
11. GC-C (guanylate cyclase-C)
12. GPCRs (G protein-coupled receptors)
13. IBD (inflammatory bowel disease)
14. IBS (irritable bowel syndrome)
15. IBS-D (inflammatory bowel disease with diarrhea)
16. KOR (κ-opioid receptor)
17. MOR (μ-opioid receptor)
18. RCT (randomized controlled trial)
19. SCFA (short-chain fatty acid)
20. SNRI (serotonin norepinephrine reuptake inhibitor)
21. SSRI (selective serotonin reuptake inhibitor)
22. TCA (tricyclic antidepressant)
23. TRP (transient receptor potential)
24. TRPV1 (transient receptor potential vanilloid 1)
25. US (United States)

Pain, defined as an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage, can be acute or chronic.1 It can originate from somatic (muscle, bone, or soft tissue) or visceral (thoracic, abdominal, or pelvic organs) structures.1 Visceral pain is one of the most challenging clinical conditions facing patients and their health care providers. It is extremely common. Abdominal pain is a key reason that patients with gastrointestinal disorders, such as inflammatory bowel disease (IBD) or disorders of gut-brain interaction (DGBI), including irritable bowel syndrome (IBS) or functional dyspepsia (FD), seek medical attention.2,3 More than 70% of patients with IBD experience abdominal pain during an acute flare,4 and between 20% and 60% report chronic abdominal pain.5 Chronic visceral pain is a hallmark of some DGBI, which affect up to 40% of adults, primarily women, worldwide.6

The diagnosis and treatment of chronic visceral pain is difficult, largely because it is poorly localized and difficult to describe due to the relatively small density of nerve terminals in the viscera and the divergent projections into the spinal cord,7 and because the pathophysiology remains incompletely understood. Chronic visceral pain is, thus, a significant burden to patients and is associated with anxiety, depression, decreased quality of life, and increased direct and indirect health care costs.5,8,9 IBS alone is estimated to cost the United States (US) ∼US $350 million each year for outpatient clinic visits, not including diagnostic testing, medications, nonpharmacologic therapies, or indirect costs due to lost productivity.10 Unfortunately, these challenges have been further amplified by the opioid crises.11,12 This highlights the continued need for advances in understanding of the pathophysiology of visceral pain to enable both effective and safe therapies.

Chronic visceral pain is a disorder of the microbiota-gut-brain axis, and central and peripheral mechanisms both contribute to its pathogenesis (Figure 1). Triggers include stress, psychological comorbidities, such as anxiety or depression, diet, low-grade intestinal inflammation, and microbial dysbiosis.4,13–15 Most abdominal pain signaling originates from nociceptors (pain-sensitive neurons), called visceral primary afferent nerves, whose cell bodies lie in the dorsal root ganglia and which have pseudo-unipolar axons connecting the intestine and the spinal cord.16 Nociceptors synapse with second-order neurons in the thoracolumbar and lumbosacral spinal cord17 and thereafter with central ascending pain pathways. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways originating from the hypothalamus and midbrain.18

Figure viewer

Figure 1 Chronic visceral pain is a disorder of the gut-brain axis. Nociceptors have cell bodies that lie in the dorsal root ganglia (DRG) and pseudounipolar axons that connect the intestine and the spinal cord. These synapse with second-order neurons in the spinal cord and with central ascending pathways thereafter. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways. (Inset) At the level of the mucosa, nociceptive terminals are both mechanosensitive and chemosensitive and are stimulated by luminal factors (eg, microbial products and nutrients) as well as by host mediators released due to infection, inflammation, or tissue damage (eg, serotonin, histamine, proteases, chemokines, and cytokines). These mediators can act indirectly via the epithelium/enterochromaffin cells or can stimulate nociceptors directly if there is a breakdown in the mucosal barrier. This results in sensitization of ion channels such as TRP, resulting in increased visceral pain.

Sensitization of nociceptors, defined as a decrease in the threshold for stimulation and an increase in the magnitude of the response,19 can occur peripherally, in the central nervous system, or both. This results in hyperalgesia, a heightened response to painful stimuli, and allodynia, which is pain arising from nonpainful stimuli.19 Central sensitization may also result in comorbid pain involving different organ systems,20 a discussion of which is beyond the scope of this review.

At the level of the periphery, nociceptive nerve terminals are found in muscle and serosa as well as in the mucosa.7 Nociceptors are mechanosensitive and are stimulated by stretch or distention.16 These actions are mediated by a variety of mechanosensitive ion channels, such as the transient receptor potential (TRP) receptors, including TRP vanilloid 1 (TRPV1) and 4, and TRP ankyrin 1, the 2-pore domain potassium channel family, the degenerin/epithelial sodium channel family, including the acid-sensing ion channels 1, 2, and 3, and the piezo-type mechanosensitive ion channel component 2 (Piezo-02).21,22

Nociceptors at the mucosal level are also chemosensitive and are stimulated by luminal factors, such as microbial products and nutrients, as well as by chemical mediators released during tissue infection, inflammation, or damage. These include bacterial toxins, neurotransmitters, proteases, bioactive amines, such as histamine, and serotonin, neurotrophins, adenosine-5′-triphosphate, chemokines, and cytokines (Figure 1, inset).13,23 Luminal products can either stimulate nociceptors directly, particularly if there is associated breakdown in the mucosal barrier as seen in both IBD and IBS,24,25 or indirectly via the epithelium or enteroendocrine cells.26

Chemical compounds and luminal products can, in turn, stimulate pronociceptive G protein-coupled receptors (GPCRs) or lead to increased expression‎ and activation of ion channels, such as TRP or voltage-gated sodium and calcium channels, or can decrease potassium channel activation and expression‎, resulting in peripheral sensitization. In turn, nociceptors can release neurotransmitters, such as substance P and calcitonin gene-related peptide, which augment the inflammatory response in the periphery and activate second-order neurons in the spinal cord, leading to neurogenic inflammation13,23 (Figure 1, inset).

Building on this pathophysiological framework, this review will focus on recent advances in visceral peripheral pain neurotransmission and mechanisms that result in sensitization of afferents in patients with IBD or painful DGBI. It will discuss specific physiologic and pathophysiologic preclinical peripheral mechanisms that have been translated into receptor-based treatment approaches for visceral pain in clinical trials. Some of these treatments have targeted advances in the physiology of nociceptors or intermediary cells, or both, whereas others target new understanding of pathophysiologic mechanisms of specific disorders.

Mechanistic Advances and the Resulting TherapiesGuanylate Cyclase-C and Visceral PainGuanylate cyclase-C pharmacology and preclinical studies

The enterocyte receptor guanylate cyclase-C (GC-C) plays an essential role in fluid secretion, barrier function, and nociception. Drugs such as linaclotide and plecanatide have taken advantage of this homeostatic system to treat visceral pain. GC-C is found on the apical surface of enterocytes throughout the gastrointestinal tract and is activated by the paracrine hormones uroguanylin and guanylin.27 Activation of GC-C triggers enzymatic conversion of guanosine-5ʹ-triphosphate to guanosine 3′,5′-cyclic monophosphate (cGMP), which in turn regulates activity of the apical cystic fibrosis transmembrane conductance regulator, leading to increased luminal chloride and bicarbonate secretion and a secondary increase in intestinal motility.27 Genetic mutations in the guanylate cyclase 2C gene (GUCY2C) have been found in patients with congenital secretory diarrhea28 and may predispose patients to IBD,29 whereas dysregulated GC-C expression‎ has been implicated in the pathophysiology of both IBD30 and IBS.31 Sex differences have not been reported.32

Epithelial GC-C signaling has a key role in nociception. Linaclotide, a minimally absorbed GC-C agonist, decreased the visceral motor response to colorectal distention in both acute colitis and stress-induced models of visceral hypersensitivity. The effects of linaclotide were abolished in GC-C–knockout animals, confirm‎ing its specificity.33 Linaclotide34 or direct application of cGMP34,35 to an ex vivo preparation of nociceptor afferents decreased response to circumferential stretch in control animals as well as in acute colitis35 and in postinflammatory34 models of visceral pain. GC-C expression‎ was not found on nociceptors,34,35 suggesting its antinociceptive effects were indirect. Indeed, linaclotide34 and uroguanylin35 both stimulated cGMP release from cultured epithelial cells.35 The effects of linaclotide were abolished in ex vivo preparations where the mucosa was removed.34

These studies suggest that epithelial GC-C activation causes basolateral cGMP secretion, which decreases nociceptor activity, providing a biological mechanism for the clinical effects of GC-C agonists. We note that a recent study has challenged the dogma that enterocyte-derived cGMP is the main antinociceptive mediator of GC-C activation,36 as discussed in section 6.

Clinical trials

Linaclotide and plecanatide have been tested in multiple randomized controlled trials (RCTs) in IBS with constipation, summarized in a prior meta-analysis (for summary of all trials discussed see Table 1).37 Both were more efficacious than placebo in the effect on abdominal pain, according to the US Food and Drug Administration (FDA)-recommended end point for abdominal pain in IBS with constipation, consisting of a ≥30% improvement from baseline for ≥50% of weeks. However, delayed-release forms of linaclotide, developed based on the premise that ileocecal delivery of the drug targets abdominal pain without affecting bowel habit, were not superior to placebo over most abdominal pain measures in a phase II RCT.38

Treatment studiedConditionNo. of studiesNo. of patientsComparatorReported effect

Linaclotide, 290 μg q.d.	IBS-C	3 RCTs summarized in a meta-analysis37	2447	Placebo	RR of abdominal pain persistence = 0.79 (95% CI, 0.73–0.85)
Plecanatide, 6 mg or 3 mg q.d.	IBS-C	2 RCTs summarized in a meta-analysis37	2194	Placebo	RR of abdominal pain persistence = 0.84 (95% CI, 0.78–0.90) and 0.87 (95% CI, 0.81–0.93), respectively
Loperamide	IBS-D Unselected patients with IBS	2 RCTs54,55	24 60	Placebo Placebo	Abdominal pain score 3.0 vs −0.14, P < .05 2.2 days with abdominal pain vs 8.3 days, P < .01
Eluxadoline, 100 mg or 75 mg b.i.d.	IBS-D	4 RCTs summarized in a meta-analysis56	2758	Placebo	RR of abdominal pain persistence = 0.89 (95% CI, 0.83–0.96) and 0.95 (95% CI, 0.88–1.04), respectively
Psyllium (up to 10 g/d)	Unselected patients with IBS	2 RCTs89,90	80 178	Placebo Placebo	Abdominal pain mild or absent in 52.5% vs 57.5%, N/S RR of adequate relief of abdominal pain at 1, 2, and 3 months = 1.60 (95% CI, 1.13–2.26), 1.44 (95% CI, 1.02–2.06), and 1.36 (95% CI, 0.90–2.04), respectively
Bran (up to 10 g/d)	Unselected patients with IBS	1 RCT90	190	Placebo	RR of adequate relief of abdominal pain at 1, 2, and 3 months = 1.13 (95% CI, 0.81–1.58), 1.22 (95% CI, 0.86–1.72), and 1.70 (95% CI, 1.12–2.57), respectively
Low FODMAP diet	IBS IBD	12 RCTs summarized in a meta-analysis91 2 RCTs92,93	914 52 89	BDA dietary advice Habitual diet Sham diet Sham diet Habitual diet	RR of abdominal pain persistence = 0.78 (95% CI, 0.57–1.06) RR of abdominal pain persistence = 0.72 (95% CI, 0.47–1.10) RR of abdominal pain persistence = 0.51 (95% CI, 0.30–0.87) Abdominal pain severity score 22 vs 30, P = .098 and 36 days with abdominal pain vs 38 days, P = .78 OR for improvement in abdominal pain frequency = 2.97 (95% CI, 1.12–7.89)
Rifaximin, 550 mg t.i.d. for 2 weeks	Nonconstipated IBS	2 RCTs summarized in a meta-analysis56	1260	Placebo	RR of abdominal pain persistence = 0.95 (95% CI, 0.89–1.01
FMT	IBS with bloating Unselected patients with IBS UC	2 RCTs96,97 1 RCT98	62 165 20	Placebo Placebo Usual treatment	Abdominal pain score 2.80 vs 3.88 at baseline with FMT, P = .001, compared with 3.57 vs 3.79 at baseline with usual treatment, P = .205 Abdominal pain score 166.8 and 186.3 posttreatment with 60 mg and 30 mg FMT, respectively, vs 307.0 with placebo, P < .001 Abdominal pain score 0.9 vs 4.5 at baseline with FMT, P = .026, compared with 1.8 vs 4.9 at baseline with usual treatment, N/S
Gelsectan	IBS-D	1 RCT99	60	Placebo	Number of patients with totally to slightly unacceptable abdominal pain reduced from 67% at baseline to 0% at 4 weeks with gelsectan vs 83% to 60% with placebo, statistical significance not reported
Probiotics Combination probiotics Lactobacillus-containing strains Saccharomyces cerevisiae I-3856 Bifidobacterium-containing strains Bacillus-containing strains	All in unselected patients with IBS	32 RCTs100 11 RCTs100 5 RCTs100 3 RCTs100 3 RCTs100	3469 1183 1482 389 212	Placebo Placebo Placebo Placebo Placebo	RR of abdominal pain persistence = 0.72 (95% CI, 0.64–0.82) RR of abdominal pain persistence = 0.59 (95% CI, 0.45–0.76) RR of abdominal pain persistence = 0.64 (95% CI, 0.45–0.90) RR of abdominal pain persistence = 0.78 (95% CI, 0.64–0.95) RR of abdominal pain persistence = 0.33 (95% CI, 0.23–0.47)
Ketotifen (titrated from 2 mg to 6 mg b.i.d.)	Unselected patients with IBS	1 RCT109	60	Placebo	7% of patients reporting severe abdominal pain vs 28%, P = .02
Ebastine 20 mg o.d.	Unselected patients with IBS Nonconstipated IBS	1 RCT110 1 RCT111	55 202	Placebo Placebo	Relief of abdominal pain in 41% vs 20%, P = .19 ≥30% improvement in abdominal pain in 37% vs 25%, P = .081
Disodium cromoglycate, 600 mg/d	IBS-D	1 RCT112	43	No treatment	≥50% improvement in abdominal pain in 77% vs 28%, P = .002
Peppermint oil (usually 2 capsules t.i.d.)	Unselected patients with IBS	7 RCTs summarized in a meta-analysis119	748	Placebo	RR of abdominal pain persistence = 0.76 (95% CI, 0.62–0.93)
Red pepper (capsaicin)	Unselected patients with IBS FD	1 RCT120 1 RCT121	50 30	Placebo Placebo	Abdominal pain score 1.9 vs 2.7 at baseline with red pepper, compared with 2.3 vs 2.4 at baseline with placebo, reported as “statistically significant” Abdominal pain score 1.61 posttreatment vs 2.37, P < .05
Alosetron, 1 mg b.i.d.	IBS-D	6 RCTs summarized in a meta-analysis56	2606	Placebo	RR of abdominal pain persistence = 0.83 (95% 0.78–0.88)
Ramosetron, 5 μg or 2.5 μg o.d.	IBS-D	5 RCTs summarized in a meta-analysis56	1928	Placebo	RR of abdominal pain persistence = 0.82 (95% CI, 0.75–0.89) and 0.75 (95% CI, 0.65–0.85), respectively
Ondansetron, 12 mg q.d, bimodal release or titrated up or down from 4 mg o.d.	IBS-D	3 RCTs summarized in a meta-analysis127	327	Placebo	RR of abdominal pain persistence = 0.95 (95% CI, 0.74–1.20)
Tegaserod, 6 mg b.i.d.	IBS-C FD	Pooled analysis of 4 RCTs128 2 RCTs129	2886 1360 1307	Placebo Placebo Placebo	OR for abdominal pain response = 1.38 (95% CI, 1.14–1.67) Abdominal pain response rate 44.9% vs 40.0%, P = .027 Abdominal pain response rate 44.0% vs 42.3%, P = .51
SSRIs (eg, escitalopram, 10 mg o.d.)	Unselected patients with IBS FD	5 RCTs summarized in a meta-analysis132 1 RCT133	262 195	Placebo Placebo	RR of abdominal pain persistence = 0.82 (95% CI, 0.58–1.16) Upper abdominal pain score 1.4 posttreatment vs 1.2, N/S
TCAs (eg, amitriptyline, 10–30 mg o.d., or imipramine, 50 mg o.d.)	Unselected patients with IBS FD	4 RCTs summarized in a meta-analysis132 1 RCT134 2 RCTs133,135	171 463 194 107	Placebo Placebo Placebo Placebo	RR of abdominal pain persistence = 0.53 (95% CI, 0.34–0.83) OR for ≥30% improvement in abdominal pain = 1.66 (95% CI, 1.12–2.46) Upper abdominal pain score 1.1 post-treatment vs 1.2, N/S Epigastric pain score 0.96 vs 1.24 at baseline with imipramine, P = .026, compared with 0.96 vs 1.13 at baseline with placebo, P = .13
SNRIs (eg., venlafaxine 150 mg o.d.)	Unselected patients with IBS	1 RCT136	30	Placebo	Frequency of abdominal pain or discomfort score 3.87 vs 4.93, P = .03
Oloroinab, 10 mg to 100 mg t.i.d.	IBS with abdominal pain Crohn’s disease with abdominal pain	1 RCT147 1 randomized, open-label study148	273 14	Placebo N/A	56.5%, 59.7%, and 56.7% of 10 mg, 25 mg, and 50 mg t.i.d., respectively, achieved a ≥30% improvement in abdominal pain vs 52.9% with placebo, N/S
					Change in abdominal pain score from baseline of −4.61 with 25 mg t.i.d. and −4.57 with 100 mg t.i.d.
Pregabalin, 75 mg o.d., or titrated up from 75 mg b.i.d.	Unselected patients with IBS FD	1 RCT154 1 RCT155	85 72	Placebo Placebo	Abdominal pain score 28 posttreatment vs 40, P = .008 Epigastric pain score 3.0 posttreatment vs 4.0, P = .01

Table 1

Summary of Evidence for Efficacy of Available Treatments Directed Against Peripheral Mechanisms of Abdominal Pain in Their Effect on Abdominal Pain as an End Point

BDA, British Dietetic Association; b.i.d., twice daily; CI, confidence interval; IBS-C, IBS with constipation; N/A, not applicable; N/S, not significant; o.d., once daily; OR, odds ratio; q.d., once daily; RR, relative risk; t.i.d., 3 times daily.

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Peripherally Acting Opioids and Visceral PainPharmacology and preclinical studies

Opioids signal through 4 GPCRs: μ-opioid receptors (MORs), δ-opioid receptors (DORs), κ-opioid receptors (KORs), and nociceptin opioid receptors.39 The analgesic effect of conventional opioids can be strong (eg, oxycodone, morphine) or weak (eg, codeine) and predominantly result from activation of MORs, although DORs and KORs also play a role. On nociceptors, these receptors trigger GPCR-Gi/o protein signaling leading to the recruitment of multifunctional intracellular proteins, called β-arrestins, and sustained signaling by endosomes.40 This signaling modulates ion channels and, ultimately, inhibits action potential firing. Receptor expression‎ is increased in inflammatory conditions, including active IBD, possibly leading to altered signaling.41

Conventional opioids can exhibit potent analgesic actions, particularly for acute pain, but are limited by their adverse effect profile, including cognitive impairment, respiratory depression, nausea, constipation, and addictive potential.42 Analgesic tolerance leads to dose escalation and consequently greater risk of these potentially life-threatening adverse effects. Dose escalation is also implicated in the development of a paradoxical switch in signaling, leading to opioid-induced hyperalgesia, a poorly understood condition.43 The opioid crisis has hastened the search for safer alternatives, including peripherally restricted opioids that lack addictive potential and central adverse effects such as respiratory depression and cognitive impairment.

Strategies to develop peripherally acting opioids are being explored to identify safe, yet effective, analgesics for visceral pain. Access to the central nervous system can be restricted, for example, by creating charged molecules, and several compounds display peripheral analgesic actions,44,45 including loperamide, a MOR agonist.46 To date, however, these do not exhibit sufficient analgesic effects to be clinically useful to treat visceral pain.

Another strategy is to target opioid receptor heterodimers, such as eluxadoline,47 a MOR agonist and DOR antagonist with weak affinity for KORs. MORs and DORs are coexpressed on nociceptors innervating the intestine, and eluxadoline shows high binding affinity for MOR/DOR heterodimers in cell assays48 and functional interaction between receptors. However, there has been sparse mechanistic study in whole-animal models to clarify the role of this interaction further.49

There are other promising strategies to develop safe opiates, such as enhancing endogenous opioids (eg, enkephalinase inhibitors), by developing pH-sensitive opioid analogues,50 which are only active at sites of inflammation and thus lack the adverse effect profile and addictive potential of conventional opioids. Combinations of subthreshold opioids and cannabinoid receptor 1 (CB1) agonists can provide strong analgesia51 without adverse effects. Novel delivery systems using nanoparticles of between 1 and 100 nm in diameter, containing opioid cargoes,52 target intracellular signaling in endosomes and can be delivered intrarectally to act locally within the inflamed colon. To date, most of these strategies are based on preclinical studies and none have been tested adequately in humans. Finally, female rodents are less sensitive to opiate analgesia,53 and whether these strategies have sex-specific effects would be important to eval‎uate.

Clinical trials

Few trials have been conducted with new opioid-related drugs in visceral pain, largely due to the negative impact of the opioid crisis. Despite widespread use of loperamide in clinical practice, there is little evidence for this. One 13-week RCT, recruiting patients with IBS with diarrhea (IBS-D), reported pain scores were significantly lower with loperamide.54 In a second 3-week trial that recruited IBS of all subtypes, the number of painful days was reduced significantly with loperamide, but only in patients with alternating bowel habit.55 Both trials used historical definitions of IBS, did not conform to guidance for design of treatment trials in DGBI, and many participants did not report abdominal pain at all. More rigorous trials of loperamide are needed, although it is unlikely these will ever be conducted.

In contrast, eluxadoline has been tested rigorously in phase III RCTs at 2 doses, 75 mg or 100 mg twice daily, with data pooled in a prior meta-analysis.56 Only 100 mg twice daily was superior to placebo for the FDA-recommended end point for abdominal pain, but benefit was modest. In addition, there have been safety issues, with episodes of acute pancreatitis and sphincter of Oddi dysfunction reported.

The Microbiome and Visceral PainAdvances in pathophysiology

The involvement of gut microbiota in the development of visceral pain is largely based on preclinical studies measuring pain thresholds after transfer of human stool microbiota into germ-free rodents or administration of live biotherapeutics (probiotics) or antibiotics, or both, in rodent models. For instance, germ-free rats colonized with stool microbiota from individuals with IBS display decreased pain thresholds in response to rectal distention.57 Further insights have been gained from studies involving gnotobiotic mice, revealing the role of commensal microbes in maintaining normal excitability of gut intrinsic neurons.58

Perturbing the gut microbiome during early life using vancomycin leads to visceral hypersensitivity in rats.59 Conversely, administration of live biotherapeutics, such as Faecalibacterium prausnitzii, Lactobacillus paracasei NCC2461, or Lactobacillus GG, reduces visceral hypersensitivity and intestinal permeability in preclinical models that alter the early-life microbiome.60,61 Unlike in early life, antibiotic administration improves visceral hypersensitivity in adult mice,62 suggesting potential age-dependent effects of the microbiome.

Interestingly, visceral pain responses to colorectal distention vary across the estrous cycle in female mice, but this effect is lost in germ-free animals. Ovariectomy caused visceral hypersensitivity in specific pathogen-free, but not germ-free mice, suggesting an interaction between sex hormones, visceral pain, and the microbiome.63

Building on insights from animal models, human studies exploring fecal microbiome changes in patients with IBS have found specific taxa that positively (Proteobacteria)64 or negatively (Bifidobacterium spp) correlate with the severity of pain.65 Although human microbiome studies have focused largely on the colon, changes in small-intestinal microbial composition, rather than bacterial numbers, appear to differentiate patients with abdominal pain from healthy controls.66 However, the role of small-intestinal microbiota in the pathophysiology of abdominal pain remains unclear. Together, although findings from preclinical models and human studies underscore a role of the gut microbiome, whether these changes are causal to the development of visceral hypersensitivity or a consequence of changes in diet and gastrointestinal motility is unknown.

Gut microbiota-derived metabolites, neurotransmitters, toxins, and cell wall components have emerged as potential factors underlying the pathophysiology of visceral hypersensitivity. These bioactive compounds can (1) sensitize sensory neurons indirectly by stimulating either enteroendocrine cells, which release serotonin, or immune cells, which release chemokines and cytokines, both of which act on distinct neuronal populations, (2) disrupt the intestinal barrier, allowing passage of potentially noxious stimuli, and (3) activate sensory neurons directly, particularly in instances where barrier function is compromised (Figure 2). Most bacteria-derived compounds are pleiotropic, acting via multiple signaling pathways. Thus, they exert wide-ranging effects. Furthermore, gut microbiota can both synthesize and use neurotransmitters, encompassing excitatory, such as glutamate, histamine, dopamine, and norepinephrine, and inhibitory neurotransmitters, such as γ-aminobutyric acid (GABA).67 These neurotransmitters allow intercommunication among microbiota members and the host.

Figure viewer

Figure 2 Mechanisms underlying gut microbiome-driven visceral nociception. Gut microbiome-derived products can sensitize peripheral nociceptors directly or act indirectly by stimulating immune cells or enterochromaffin cells, or both, to release cytokines, chemokines, or serotonin, or a combination of these, respectively. The gut microbiome can also modulate intestinal barrier function by altering the luminal bile acid and protease pool or through metabolites such as butyrate. AHR, aryl hydrocarbon receptor; CA, carboxylic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; FFAR, free fatty acid receptor; FXR, farnesoid X receptor; GPR35, G protein-coupled receptor 35; LCA, lithocholic acid; LPS, lipopolysaccharide; LTS, leukotrienes PAMPs, pathogen-associated molecular patterns; PAR2, protease activated receptor 2; PGN, peptidoglycan; TGR5, Takeda G protein-coupled receptor 5; TLR, Toll-like receptor.

Enterochromaffin cells are the primary cell type responsible for peripheral serotonin production. They are polymodal chemosensors, capable of detecting specific luminal signals via an array of receptor pathways and translating them to the enteric nervous system by modulating serotonin-sensitive primary afferent nerves.68 Catecholamine neurotransmitters, such as norepinephrine and dopamine, initiate the adrenoceptor alpha 2A (Adrα2A) and the transient receptor potential cation channel subfamily C member 4 (TRPC4) signaling cascade.

On the other hand, short-chain fatty acids (SCFAs) and branched-chain fatty acids, such as isovaleric acid and, to a lesser extent, butyrate, activate the olfactory receptor 558 and P/Q type Cav channel within enterochromaffin cells.68 A multitude of bacterial metabolites, including butyrate, also augment serotonin synthesis within enterochromaffin cells.69 The role played by serotonin in modulating visceral pain, as well as the critical role of enterochromaffin cells in isovalerate-induced visceral hypersensitivity, is discussed further below.

Pathogen-associated molecular pattern molecules, which include bacterial cell wall components such as lipopolysaccharide, bind to pattern recognition receptors such as Toll-like receptors, are present on immune cells and sensory neurons. Pathogen-associated molecular pattern molecules contribute to visceral hypersensitivity by influencing nociceptors directly or by affecting immune cells indirectly, leading to peripheral sensitization.70,71 Diet-derived metabolites from bacterial fermentation, such as SCFAs, indole and indole derivatives, and kynurenine, also modulate visceral nociception. Butyrate exerts antinociceptive effects72 via peroxisome proliferator-activated receptors suppressing the activity of nuclear factor κ-light-chain-enhancer of activated B cells, involved in pain and inflammation.73,74

Butyrate also augments intestinal barrier function via activation of hypoxia inducible factor,75 regulates immune cells via free fatty acid 2/3 receptors,76 and drives epigenetic changes. Tryptophan is converted by microbes to kynurenic acid77 or to indole derivatives,78 both of which exert anti-inflammatory effects via G protein-coupled receptor 35 and aryl hydrocarbon receptor, respectively,79,80

Gut bacteria play an important role in determining the luminal bile acid and protease pool. Bile acid metabolites, including deoxycholic acid, regulate pain through the activation of G protein-coupled bile acid receptor 1, and are present in both primary sensory neurons and macrophages. Proteases contribute to visceral hypersensitivity by targeting intestinal barrier function81 as well as by signaling directly through protease activated receptor 2, present on neurons.82 The luminal protease pool depends on the balance between bacterial proteases83 and suppression of host proteases by bacteria harboring β-glucuronidases.81

The identification of distinct microbiota-driven mechanisms opens the door for novel therapeutic strategies. Currently, microbiota-targeted interventions largely focus on augmenting intestinal barrier function. In preclinical studies, fiber maintained both microbial diversity and barrier function,84 and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) was found to preserve barrier function by decreasing lipopolysaccharide-mediated mast cell activation.85

Clinical trials

There are a multitude of methods to manipulate the microbiome, and thereby microbial metabolites, as a means of treating abdominal pain. SCFA enemas have been studied in IBD, but trials have not reported an effect on abdominal pain.86–88 Fiber has been assessed in IBS, but few trials report abdominal pain outcomes.89,90 One 12-week RCT found there was no benefit of psyllium, a soluble fiber, over placebo,89 but in another trial of psyllium, bran, or placebo, significant improvements in abdominal pain occurred with both psyllium and bran at several time points.90

A network meta-analysis of 12 trials studied the effect of a low FODMAP diet on abdominal pain.91 It was superior to a sham diet but was not superior to standard British Dietetic Association dietary advice for IBS or habitual diet. In contrast, in a RCT comparing a 4-week low FODMAP diet with a sham diet in patients with quiescent IBD with persistent gastrointestinal symptoms, abdominal pain severity and days with abdominal pain did not differ.92 In another 6-week trial of a low FODMAP diet vs normal diet in patients with IBD in remission with ongoing gastrointestinal symptoms, response for abdominal pain frequency, but not severity, was significantly higher with the low FODMAP diet.93 Abdominal pain response rates with rifaximin, a minimally absorbed antibiotic, according to the FDA-recommended end point, were reported in a meta-analysis.56 There was no benefit with rifaximin over placebo.

Although there have been multiple RCTs of fecal microbial transplant (FMT) in both IBS and IBD, summarized in prior meta-analyses,94,95 few report impact of FMT on abdominal pain. Two RCTs of FMT in IBS studied this end point.96,97 One 12-week trial of a single FMT via nasojejunal tube in IBS with predominant bloating reported abdominal pain scores were significantly reduced.96 In the second RCT, 30 mg or 60 mg of a single FMT via gastroscopy led to a significant reduction in abdominal pain at 3 months vs placebo.97 One RCT comparing FMT with usual therapy in active ulcerative colitis reported abdominal pain scores improved significantly with FMT at 2 weeks compared with baseline, but also improved significantly in the usual therapy arm.98

Gelsectan, a prebiotic with mucoprotective and bifidogenic effects, which may reinforce the intestinal barrier, was studied in 1 crossover trial.99 The number of participants with totally to slightly unacceptable abdominal pain was reduced from baseline to 4 weeks compared with placebo. Finally, in a meta-analysis certain combinations of probiotics, Lactobacillus-containing strains, Saccharomyces cerevisiae I-3856, and Bifidobacteria- and Bacillus-containing strains improved abdominal pain, but certainty in the evidence was low to very low across the studies, with heterogeneity between individual trials in most analyses.100

Histamine and Visceral PainPharmacology and preclinical studies

Histamine functions as a paracrine signaling molecule that can activate nociceptors in the gastrointestinal tract (Figure 3). It is a member of the biogenic amine family and is synthesized from l-histidine exclusively by l-histidine decarboxylase.101 Histamine signaling to nociceptors in the gut could originate from 2 sources: intestinal tissue or the lumen. In tissue, it is stored in high concentrations, predominantly in mast cells, but also in basophils and eosinophils. However, other cells in the gut also express histidine decarboxylase, including macrophages, neutrophils, platelets, and dendritic cells, and can synthesize and release histamine but do not store it.102 In the lumen of the gastrointestinal tract, there are 3 possible sources: synthesis by microbiota, ingestion of histamine-rich foods, and histamine released from tissues that permeates into the lumen.

Figure viewer

Figure 3 Novel mechanisms causing increased histamine signaling to intestinal nociceptors. (A) This schema shows that after combined food antigen (red triangle) and acute self-limiting colitis or combined food antigen and psychological stress exposure, reexposure to food antigen alone triggers increased IgE release within the intestine (which is not systemic), causing mast cell degranulation within the intestinal wall. The ensuing histamine release causes nociceptor sensitization and increased pain signaling. (B) This schema shows that ingestion of poorly absorbed complex carbohydrates (CHO) (eg, FODMAPs) can stimulate microbial production of histamine. Patients with Klebsiella aerogenes produce up to 100 times more histamine than those lacking this bacterium in their stool samples. Luminal histamine stimulates H4 and H1 receptors, leading to mast cell degranulation with ensuing nociceptor sensitization and increased pain signaling. DRG, dorsal root ganglia.

Histamine is metabolized by 2 dominant pathways, histamine-N-methyltransferase and diamine oxidase,103 resulting in N-methyl histamine and imidazole acetaldehyde metabolites, respectively. These metabolites also exhibit biological activity (eg, N-methyl histamine), and the preponderance of the pathways may differ between mast cells and microbiota.

Histamine, and possibly some metabolites, can activate 4 GPCRs, H1 to H4.101 These GPCRs signal intracellularly via Gq and cyclic adenosine monophosphate to modulate passive and voltage-gated ion channels on nociceptors and other effector pathways in nonneuronal cells. The distribution of these receptors within the gut suggests histamine activates pain signaling directly through activation of neurons and indirectly via immune cell activation (Figure 3).

In humans,104 H1 receptors are found on connective tissues cells, immune cells, enterocytes, smooth muscle cells, and nerves, H2 receptors are found on gastric parietal cells, enterocytes, immunocytes, enteric nerves, and smooth muscle cells, and H4 receptors are expressed on immune cells, blood vessels, nerves, and enterocytes. H3 receptors have yet to be identified in humans.

Previous studies highlight the role of histamine in patients with IBS, demonstrating increased levels of histamine (and proteases) in mucosal biopsy specimens from patients compared with healthy controls, evidence of mast cell activation, and the ability of histamine in tissue supernatants from patients to exaggerate activation of rodent and human nociceptive neurons.105 Sex differences have not been described. More recent studies show increases in duodenal eosinophils in patients with FD, another source of tissue histamine, implicating a role in abdominal pain in this disorder.106 The triggers resulting in abnormal mast cell-histamine signaling observed in these patients have been unclear, but recent preclinical studies suggest multiple possible etiologies, as outlined below.

When mice develop a self-limiting bacterial colitis and are exposed simultaneously to a food antigen, and then reexposed to the food antigen alone after resolution of infection, they lose oral tolerance to the food antigen.14 This leads to visceral hypersensitivity and mast cell activation with histamine release. This exaggerated pain signaling was blocked by an H1 receptor antagonist, which inhibits histamine signaling to neurons, and by an IgE antibody, which prevents mast cell activation. Tissues exhibited elevated IgE levels, consistent with loss of oral tolerance, but there was no systemic increase in IgE, highlighting immune activation was confined to the intestine.

Injection of common antigens into the rectal mucosa in patients with IBS caused greater wheal and flare responses, compared with healthy volunteers, consistent with the hypothesis that some patients with IBS are sensitized to food antigens.14 Recent preliminary studies suggest psychological stress can also induce loss of oral tolerance to food antigens and lead to mast cell-histamine–mediated visceral hypersensitivity in both the small intestine and colon, a feature observed in many patients with IBS.107

Histamine production by the microbiota may be stimulated by poorly absorbed complex carbohydrates. In a study using germ-free mice to create a humanized IBS mouse model with fecal microbiota from patients with IBS and healthy controls,108 mice given fecal samples from patients with IBS who were high histamine producers, based on stool and urine samples, exhibited visceral hyperalgesia. This exaggerated pain signaling was blocked by H1- and H4- receptor antagonists, suggesting several signaling pathways were involved (Figure 3). Some of the histamine in the luminal samples could originate from the host (eg, mast cell degranulation). However, high histamine producers were found to have microbial species, including Klebsiella aerogenes, in their stool that could make up to 100 times more histamine than those without.

Clinical trials

Drugs targeting histamine receptors or stabilizing mast cells have not been well studied in gastrointestinal diseases. An 8-week trial of ketotifen, a H1-receptor antagonist, in IBS reported a significant improvement in abdominal pain over placebo.109 Ebastine, another H1-receptor antagonist, has been assessed in IBS.110,111 A 12-week proof-of-concept RCT found rates of relief of abdominal pain were numerically higher with ebastine, but not significantly so. In a subsequent phase IIb placebo-controlled trial, rates of abdominal pain improvement were higher with ebastine, although this was not significant.111 The effect of the mast cell stabilizer disodium cromoglycate on abdominal pain was studied in a RCT in IBS-D.112 In this 6-month study, compared with no treatment, significantly more patients randomized to disodium cromoglycate experienced abdominal pain improvement.

Transient Receptor Potential Vanilloid 1 and Visceral PainPharmacology and preclinical studies

TRPV1 is a nxxxxonselective ligand-gated cation channel that is highly enriched in gastrointestinal tract nociceptors. It is activated by polymodal stimuli, including mechanical stretch, noxious heat, low pH, exogenous chemical irritants, such as capsaicin (the active ingredient in chili peppers), and endogenous lipid metabolites of arachidonic acid (eg, the endocannabinoid anandamide113). Selective ablation of colon-projecting TRPV1-expressing neurons decreased nociception in response to colorectal distention in mice,22 highlighting its critical role in visceral pain. Estrogens can modulate lumbosacral dorsal root ganglia TRPV1 expression‎, suggesting a potential mechanism for sex differences in visceral pain.114

Sensitization of TRPV1 by inflammatory mediators, such as histamine,110 is one of the key pathways in mediating peripheral visceral hypersensitivity, as discussed above. However, TRPV1 expression‎ does not necessarily correlate with receptor sensitization. For example, in patients with IBS who were hypersensitive to rectal distention, rectal application of capsaicin caused increased pain perception. No change in TRPV1 expression‎ was noted when comparing hypersensitive and normosensitive patients with IBS, suggesting that although TRPV1 expression‎ is important, additional factors, such as receptor sensitization or central factors, or both, are necessary in mediating visceral pain.115

Although most of the studies have focused on TRPV1 sensitization in IBS and FD,113 TRPV1 may also play a role in chronic visceral pain in patients with IBD in remission. Rectal TRPV1 expression‎ was increased in patients with IBD in endoscopic remission with chronic visceral pain and correlated with patient-reported symptoms.116 Visceral hyperalgesia was TRPV1-dependent in postinflammatory mice,117 and they also displayed increased SCFA-producing microbiota and stool SCFA content. These microbial-derived SCFAs increased capsaicin-evoked calcium responses in the postinflammatory state, suggesting that microbial metabolites can sensitize TRPV1.118

Clinical trials

Peppermint oil, as well as being a smooth muscle relaxant, may have effects on TRPV1 signaling. A meta-analysis showed it was more efficacious than placebo for abdominal pain.119 However, benefit was modest, with heterogeneity between studies, and most trials did not use FDA-recommended end points. Although capsaicin stimulates the TRPV1 receptor, leading to worsening abdominal pain, repeated administration down-regulates the receptor. A 6-week trial in IBS showed abdominal pain scores were significantly lower, compared with baseline, in patients receiving red pepper pills compared with those receiving placebo.120 A similar 5-week study in FD demonstrated a significant reduction in epigastric pain scores with red pepper vs placebo.121 However, patients in both trials randomized to red pepper dropped out due to pain exacerbations.

Serotonin (5-Hydroxytryptamine) and Visceral PainPharmacology and preclinical studies

The monoamine neurotransmitter 5-hydroxytryptamine (5HT) plays an integral role in initiation of intrinsic gut reflexes regulating motility, secretion, and vasodilation. It also participates in the pathogenesis of visceral pain via afferent nerve 5-HT3 and 5-HT4 receptors; drugs that modulate these receptors have been used extensively in the treatment of visceral hypersensitivity.122 The actions of 5HT are terminated by the serotonin selective reuptake transporter, a peripheral target of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and serotonin norepinephrine reuptake inhibitors122 (SNRIs).

Genetic polymorphisms in the 5-HT3 receptor and the serotonergic synthetic enzyme, tryptophan hydroxylase, are associated with increased IBS susceptibility, whereas SSRI transporter polymorphisms are associated with both IBS and FD.123 Multiple studies report changes in 5HT synthesis, reuptake, and release in IBS,124 suggesting dysregulated 5HT signaling contributes to the pathophysiology of visceral pain. Surprisingly, few studies eval‎uating the role of TCAs in visceral pain have been performed in rodent models.

Although 5HT can be secreted by enteric neurons and mucosal mast cells, most of the body’s 5HT is synthesized and stored by enterochromaffin cells.122 Enterochromaffin cells are electrically excitable, and display axon-like basal processes, forming functional connections with extrinsic and intrinsic afferent neurons, termed neuropods.68,125 Enterochromaffin cells function as luminal sensory transducers, releasing 5HT in response to dietary nutrients and microbial products, as well as mucosal distortion via mechanosensitive Piezo-02 channels.126 5HT release by enterochromaffin cells, thus initiates intrinsic gut reflexes and stimulates extrinsic nerves.

A recent study eval‎uated the role of a mucosal afferent-enterochromaffin cell circuit in the pathogenesis of visceral hypersensitivity using transgenic mice,26 where enterochromaffin cells could be activated or silenced selectively. Direct activation of enterochromaffin cells elicited 5HT release and was sufficient to cause both acute and chronic visceral hypersensitivity to colorectal distention. Remarkably, activation of enterochromaffin cells was sufficient to elicit anxiety-like behavior in mice. These effects were inhibited by the 5HT3 antagonist alosetron, which decreased mucosal afferent activity. Conversely, silencing activity of enterochromaffin cells attenuated 5HT release and visceral hypersensitivity mediated by the microbial metabolite, isovalerate, in male mice. The mucosal afferent-enterochromaffin cell circuit demonstrated high tonic activity in female, but not male, mice suggesting a sex-specific contribution to pain signaling. Together, these data demonstrate that the enterochromaffin cell-mucosal afferent circuit plays an essential role in pathogenesis of visceral hypersensitivity.26

It is possible that the GC-C pathway also regulates 5HT secretion from enterochromaffin cells. GC-C is expressed not only by enterocytes but also by a subtype of monoamine synthesis-expressing neuropods enriched in the proximal intestine of mice.36 GC-C enriched neuropods formed functional connections with nociceptors in cocultures and caused spontaneous nociceptor activation, which was abolished by linaclotide. The antinociceptive effects of linaclotide on the response to colorectal distention were lost in mice that were deficient in neuropod GC-C.36 Thus, it is possible that enterochromaffin GC-C activation regulates 5HT tone, but whether this mechanism is active in vivo is unclear.

Clinical trials

The efficacy of the 5HT3-receptor antagonists alosetron and ramosetron, according to the FDA-recommended end point for abdominal pain, has been reported in multiple trials in IBS-D, pooled in a meta-analysis.56 Ramosetron, 2.5 μg daily and 5 μm daily, and alosetron, 1 mg twice daily, were superior to placebo, although alosetron has been associated with ischemic colitis. Varying doses of ondansetron, another 5HT3-receptor antagonist with a long history of safety, were assessed in 3 trials in IBS-D, summarized in another meta-analysis.127 The drug was not superior to placebo for pain.

For 5HT4-receptor agonists, in a pooled analysis of data from 4 RCTs in IBS, tegaserod, 6 mg twice daily, was more efficacious for pain than placebo.128 In two 6-week trials of tegaserod in FD, 6 mg twice daily was superior to placebo for abdominal pain in 1 RCT but not the other.129 Safety issues arising from cardiovascular and cerebrovascular ischemic events led to the withdrawal of tegaserod. Although it was reintroduced briefly, tegaserod is now no longer available. Prucalopride was assessed in chronic constipation and was efficacious,130 but no RCTs report its efficacy in improving abdominal pain, and it has never been tested in IBS or FD.

Although SSRIs, TCAs, and SNRIs are antidepressants, in the context of treating abdominal pain, they act as gut-brain neuromodulators involving, at least in part, 5-HT131; discussion of the central actions of these compounds is beyond the scope of this review. SSRIs have been assessed in IBS and FD, with no impact on abdominal pain in IBS in a prior meta-analysis,132 and a reduction in pain scores in FD in a single RCT of escitalopram, 10 mg once daily, but with no benefit over placebo.133 TCAs, however, were more efficacious than placebo for abdominal pain in IBS in a meta-analysis of 4 RCTs132 and more recently in a 6-month trial in 463 patients.134 In one 12-week trial in refractory FD, imipramine led to a significant reduction in epigastric pain scores vs placebo,135 but another trial of amitriptyline demonstrated no benefit.133 The SNRI venlafaxine was assessed in a single 12-week RCT in IBS; abdominal pain frequency scores were reduced significantly compared with placebo.136 An RCT of FD did not report its effect on abdominal pain.137

Cannabinoids and Visceral PainPharmacology and preclinical studies

Cannabinoids are widely used alternative therapies to treat abdominal pain in both IBD and IBS.138,139 The actions of cannabinoids are mediated via the endocannabinoid system, which regulates gastrointestinal motility, secretion, immune function, intestinal permeability, and visceral hypersensitivity.140

The classical components of the endocannabinoid system are the endogenous cannabinoid ligands, anandamide, and 2-arachidonoylglycerol, as well as their biosynthetic and degradative enzymes. These are found throughout the microbiota-gut-brain axis, including the epithelium, enterochromaffin cells, enteric nervous system, and immune system, as well as extrinsic afferent nerves, where they primarily exert an antinociceptive effect. Anandamide is also an agonist at TRPV1. Thus, endocannabinoids have both pronociceptive and antinociceptive effects, depending on the receptor.140 Interestingly, commensal bacteria can produce endocannabinoid-like molecules,141 although whether a microbial source of endocannabinoid-like molecules plays a role in visceral hypersensitivity is unknown.

In animal models of stress-induced visceral hypersensitivity and in postinflammatory models, CB1 and CB2 agonists decrease the visceromotor response to colorectal distention.140,142–144 Endocannabinoids can either exert their antinociceptive actions directly via CB1 and CB2 receptors expressed on nociceptors142,145 or indirectly via down-regulation of mast cell or macrophage activation.140 However, clinical use of cannabinoids is hampered by psychotropic adverse effects. Accordingly, there has been interest in synthesizing peripherally restricted cannabinoid receptor agonists.142–144

A recent preclinical study of the peripherally restricted CB2 receptor agonist, olorinab, was performed in rodent models of acute colitis and postinflammatory visceral pain.142 Olorinab reversed the colitis-induced hypersensitivity to colorectal distention in both the acute and postinflammatory state; no effects on visceral pain were seen when olorinab was given to controls. Olorinab was able to decrease mechanosensitivity of ex vivo afferent nerves in a dose-dependent manner, both in acute colitis and in the postinflammatory state, although CB2 expression‎ was not up-regulated in afferent nerves compared with controls.142 Unfortunately, only male mice were eval‎uated in this study, although CB2 expression‎ is increased in female patients with IBS.146 These data suggest CB2 receptors on visceral afferents are sensitized by inflammation and, in turn, play a regulatory anti-nociceptive role.

Clinical trials

In a 12-week phase II dose-ranging study of olorinab in IBS, the proportion of patients experiencing improvement in abdominal pain was not significantly higher with any dose studied.147 However, in those with moderate to severe pain at baseline, abdominal pain scores were significantly improved with 50 mg 3 times daily. No placebo-controlled trials of this drug in IBD have been conducted, although an 8-week open-label randomized study recruiting patients with Crohn’s disease who reported abdominal pain found a significant reduction in pain scores from baseline with olorinab.148 There is no evidence for other drugs acting on cannabinoid receptors for treating abdominal pain in gastrointestinal disorders.149

γ-Aminobutyric Acid and Visceral PainPharmacology and preclinical studies

Functional GABA receptors have been identified in the nerve terminals of colonic afferents. The activation of GABA receptors (GABAA and GABAB) by endogenous GABA decreases sensitivity of colonic afferents, whereas GABAA activation also reduces visceral pain perception.150 Functional GABAergic transmission has also been found in nociceptors, producing strong analgesic effects.151 In addition to endogenous production, certain bacteria expressing glutamate decarboxylase, can produce GABA from glutamate.67 In rodent models, GABA-producing bacteria have an analgesic effect in stress-induced152 and fecal-retention153 models of visceral hypersensitivity.

Clinical trials

There has been 1 RCT of pregabalin in both FD and IBS, but no trials in other painful gastrointestinal disorders and no trials of gabapentin. Abdominal pain scores were significantly lower in patients assigned to titrated pregabalin vs placebo in a 12-week trial in IBS.154 Similarly, pregabalin, 75 mg daily, was superior to placebo for epigastric pain scores in an 8-week trial in FD.155

Conclusions

Chronic visceral pain represents a substantial burden to patients. Despite the potential for the evidence-based treatments described above, a need remains for the development of novel therapeutics to treat sensitization of peripheral pain pathways effectively. Future directions should include the identification of microbial vs host sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), similar to current work eval‎uating histamine (Figure 4).

Figure viewer

Figure 4 Areas for future investigation in peripheral mechanisms of visceral pain. There is a need to identify peripheral mechanisms underlying visceral pain and develop novel therapeutic agents to treat patients. Identification of microbial vs host sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), is one such mechanistic area. Eval‎uation of the relative contribution of each pathophysiologic mechanism to nociceptor sensitization in individual patients, and thus use of combination therapies targeting these mechanisms, is key. For opiates, some promising strategies for the development of safe yet effective opiate therapies are the development of pH-sensitive opiate analogues active at the site of inflammation, use of peripherally restricted agents or subthreshold combinations of opiates, and CB1 receptor agonists. Because chronic visceral pain is more common in women, future studies should eval‎uate whether pain mechanisms are sex-specific and whether treatments should be used in a sex-specific manner. ♀, female; ♂, male.

With respect to the microbiome, research should avoid observational-based community profiling and focus on mechanistic approaches eval‎uating how microbiota or microbial products, or both, interact with nociceptors. Methods to test the relative contribution of each pathophysiologic mechanism to the sensitization of peripheral nociceptors and their role in overlapping pain syndromes in individual patients is also required. This would allow the use of specific drug combinations to target multiple mechanisms synergistically.

Given the sex bias of chronic visceral pain, future studies should eval‎uate whether pain mechanisms are sex-specific or whether treatments should be used in a sex-specific manner. Identifying whether differing or similar peripheral mechanisms are involved in the development of chronic visceral pain in patients with IBD vs painful DGBI will be important. Finally, eval‎uation of the relative contribution of peripheral vs central sensitization to symptoms would be important to individualize patient therapy. Continued multidisciplinary collaboration between clinician-scientists and bench-based scientists with the use of innovative reverse translational approaches is necessary to advance this field, identify new target pathways, and improve the clinical management of patients.

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Reviews in Basic and Clinical Gastroenterology and HepatologyVolume 166, Issue 6p976-994June 2024Open access

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Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments

Alexander C. Ford1,2,∗ ∙ Stephen Vanner3,∗ ∙ Purna C. Kashyap4 ∙ Yasmin Nasser5 ynasser@ucalgary.ca

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Abstract

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

Keywords

1. Visceral Pain
2. Inflammatory Bowel Disease
3. Irritable Bowel Syndrome
4. Histamine
5. Serotonin
6. Microbiome
7. Abdominal Pain
8. Inflammation

Abbreviations used in this paper

1. HT (5-hydroxytryptamine)
2. CB1 (cannabinoid receptor 1)
3. cGMP (guanosine 3′,5′-cyclic monophosphate)
4. DGBI (disorders of gut-brain interaction)
5. DOR (δ-opioid receptor)
6. FD (functional dyspepsia)
7. FDA (Food and Drug Administration)
8. FMT (fecal microbial transplant)
9. FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols)
10. GABA (γ-aminobutyric acid)
11. GC-C (guanylate cyclase-C)
12. GPCRs (G protein-coupled receptors)
13. IBD (inflammatory bowel disease)
14. IBS (irritable bowel syndrome)
15. IBS-D (inflammatory bowel disease with diarrhea)
16. KOR (κ-opioid receptor)
17. MOR (μ-opioid receptor)
18. RCT (randomized controlled trial)
19. SCFA (short-chain fatty acid)
20. SNRI (serotonin norepinephrine reuptake inhibitor)
21. SSRI (selective serotonin reuptake inhibitor)
22. TCA (tricyclic antidepressant)
23. TRP (transient receptor potential)
24. TRPV1 (transient receptor potential vanilloid 1)
25. US (United States)

Pain, defined as an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage, can be acute or chronic.1 It can originate from somatic (muscle, bone, or soft tissue) or visceral (thoracic, abdominal, or pelvic organs) structures.1 Visceral pain is one of the most challenging clinical conditions facing patients and their health care providers. It is extremely common. Abdominal pain is a key reason that patients with gastrointestinal disorders, such as inflammatory bowel disease (IBD) or disorders of gut-brain interaction (DGBI), including irritable bowel syndrome (IBS) or functional dyspepsia (FD), seek medical attention.2,3 More than 70% of patients with IBD experience abdominal pain during an acute flare,4 and between 20% and 60% report chronic abdominal pain.5 Chronic visceral pain is a hallmark of some DGBI, which affect up to 40% of adults, primarily women, worldwide.6

The diagnosis and treatment of chronic visceral pain is difficult, largely because it is poorly localized and difficult to describe due to the relatively small density of nerve terminals in the viscera and the divergent projections into the spinal cord,7 and because the pathophysiology remains incompletely understood. Chronic visceral pain is, thus, a significant burden to patients and is associated with anxiety, depression, decreased quality of life, and increased direct and indirect health care costs.5,8,9 IBS alone is estimated to cost the United States (US) ∼US $350 million each year for outpatient clinic visits, not including diagnostic testing, medications, nonpharmacologic therapies, or indirect costs due to lost productivity.10 Unfortunately, these challenges have been further amplified by the opioid crises.11,12 This highlights the continued need for advances in understanding of the pathophysiology of visceral pain to enable both effective and safe therapies.

Chronic visceral pain is a disorder of the microbiota-gut-brain axis, and central and peripheral mechanisms both contribute to its pathogenesis (Figure 1). Triggers include stress, psychological comorbidities, such as anxiety or depression, diet, low-grade intestinal inflammation, and microbial dysbiosis.4,13–15 Most abdominal pain signaling originates from nociceptors (pain-sensitive neurons), called visceral primary afferent nerves, whose cell bodies lie in the dorsal root ganglia and which have pseudo-unipolar axons connecting the intestine and the spinal cord.16 Nociceptors synapse with second-order neurons in the thoracolumbar and lumbosacral spinal cord17 and thereafter with central ascending pain pathways. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways originating from the hypothalamus and midbrain.18

Figure viewer

Figure 1 Chronic visceral pain is a disorder of the gut-brain axis. Nociceptors have cell bodies that lie in the dorsal root ganglia (DRG) and pseudounipolar axons that connect the intestine and the spinal cord. These synapse with second-order neurons in the spinal cord and with central ascending pathways thereafter. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways. (Inset) At the level of the mucosa, nociceptive terminals are both mechanosensitive and chemosensitive and are stimulated by luminal factors (eg, microbial products and nutrients) as well as by host mediators released due to infection, inflammation, or tissue damage (eg, serotonin, histamine, proteases, chemokines, and cytokines). These mediators can act indirectly via the epithelium/enterochromaffin cells or can stimulate nociceptors directly if there is a breakdown in the mucosal barrier. This results in sensitization of ion channels such as TRP, resulting in increased visceral pain.

Sensitization of nociceptors, defined as a decrease in the threshold for stimulation and an increase in the magnitude of the response,19 can occur peripherally, in the central nervous system, or both. This results in hyperalgesia, a heightened response to painful stimuli, and allodynia, which is pain arising from nonpainful stimuli.19 Central sensitization may also result in comorbid pain involving different organ systems,20 a discussion of which is beyond the scope of this review.

At the level of the periphery, nociceptive nerve terminals are found in muscle and serosa as well as in the mucosa.7 Nociceptors are mechanosensitive and are stimulated by stretch or distention.16 These actions are mediated by a variety of mechanosensitive ion channels, such as the transient receptor potential (TRP) receptors, including TRP vanilloid 1 (TRPV1) and 4, and TRP ankyrin 1, the 2-pore domain potassium channel family, the degenerin/epithelial sodium channel family, including the acid-sensing ion channels 1, 2, and 3, and the piezo-type mechanosensitive ion channel component 2 (Piezo-02).21,22

Nociceptors at the mucosal level are also chemosensitive and are stimulated by luminal factors, such as microbial products and nutrients, as well as by chemical mediators released during tissue infection, inflammation, or damage. These include bacterial toxins, neurotransmitters, proteases, bioactive amines, such as histamine, and serotonin, neurotrophins, adenosine-5′-triphosphate, chemokines, and cytokines (Figure 1, inset).13,23 Luminal products can either stimulate nociceptors directly, particularly if there is associated breakdown in the mucosal barrier as seen in both IBD and IBS,24,25 or indirectly via the epithelium or enteroendocrine cells.26

Chemical compounds and luminal products can, in turn, stimulate pronociceptive G protein-coupled receptors (GPCRs) or lead to increased expression‎ and activation of ion channels, such as TRP or voltage-gated sodium and calcium channels, or can decrease potassium channel activation and expression‎, resulting in peripheral sensitization. In turn, nociceptors can release neurotransmitters, such as substance P and calcitonin gene-related peptide, which augment the inflammatory response in the periphery and activate second-order neurons in the spinal cord, leading to neurogenic inflammation13,23 (Figure 1, inset).

Building on this pathophysiological framework, this review will focus on recent advances in visceral peripheral pain neurotransmission and mechanisms that result in sensitization of afferents in patients with IBD or painful DGBI. It will discuss specific physiologic and pathophysiologic preclinical peripheral mechanisms that have been translated into receptor-based treatment approaches for visceral pain in clinical trials. Some of these treatments have targeted advances in the physiology of nociceptors or intermediary cells, or both, whereas others target new understanding of pathophysiologic mechanisms of specific disorders.

Mechanistic Advances and the Resulting TherapiesGuanylate Cyclase-C and Visceral PainGuanylate cyclase-C pharmacology and preclinical studies

The enterocyte receptor guanylate cyclase-C (GC-C) plays an essential role in fluid secretion, barrier function, and nociception. Drugs such as linaclotide and plecanatide have taken advantage of this homeostatic system to treat visceral pain. GC-C is found on the apical surface of enterocytes throughout the gastrointestinal tract and is activated by the paracrine hormones uroguanylin and guanylin.27 Activation of GC-C triggers enzymatic conversion of guanosine-5ʹ-triphosphate to guanosine 3′,5′-cyclic monophosphate (cGMP), which in turn regulates activity of the apical cystic fibrosis transmembrane conductance regulator, leading to increased luminal chloride and bicarbonate secretion and a secondary increase in intestinal motility.27 Genetic mutations in the guanylate cyclase 2C gene (GUCY2C) have been found in patients with congenital secretory diarrhea28 and may predispose patients to IBD,29 whereas dysregulated GC-C expression‎ has been implicated in the pathophysiology of both IBD30 and IBS.31 Sex differences have not been reported.32

Epithelial GC-C signaling has a key role in nociception. Linaclotide, a minimally absorbed GC-C agonist, decreased the visceral motor response to colorectal distention in both acute colitis and stress-induced models of visceral hypersensitivity. The effects of linaclotide were abolished in GC-C–knockout animals, confirm‎ing its specificity.33 Linaclotide34 or direct application of cGMP34,35 to an ex vivo preparation of nociceptor afferents decreased response to circumferential stretch in control animals as well as in acute colitis35 and in postinflammatory34 models of visceral pain. GC-C expression‎ was not found on nociceptors,34,35 suggesting its antinociceptive effects were indirect. Indeed, linaclotide34 and uroguanylin35 both stimulated cGMP release from cultured epithelial cells.35 The effects of linaclotide were abolished in ex vivo preparations where the mucosa was removed.34

These studies suggest that epithelial GC-C activation causes basolateral cGMP secretion, which decreases nociceptor activity, providing a biological mechanism for the clinical effects of GC-C agonists. We note that a recent study has challenged the dogma that enterocyte-derived cGMP is the main antinociceptive mediator of GC-C activation,36 as discussed in section 6.

Clinical trials

Linaclotide and plecanatide have been tested in multiple randomized controlled trials (RCTs) in IBS with constipation, summarized in a prior meta-analysis (for summary of all trials discussed see Table 1).37 Both were more efficacious than placebo in the effect on abdominal pain, according to the US Food and Drug Administration (FDA)-recommended end point for abdominal pain in IBS with constipation, consisting of a ≥30% improvement from baseline for ≥50% of weeks. However, delayed-release forms of linaclotide, developed based on the premise that ileocecal delivery of the drug targets abdominal pain without affecting bowel habit, were not superior to placebo over most abdominal pain measures in a phase II RCT.38

Treatment studiedConditionNo. of studiesNo. of patientsComparatorReported effect

Linaclotide, 290 μg q.d.	IBS-C	3 RCTs summarized in a meta-analysis37	2447	Placebo	RR of abdominal pain persistence = 0.79 (95% CI, 0.73–0.85)
Plecanatide, 6 mg or 3 mg q.d.	IBS-C	2 RCTs summarized in a meta-analysis37	2194	Placebo	RR of abdominal pain persistence = 0.84 (95% CI, 0.78–0.90) and 0.87 (95% CI, 0.81–0.93), respectively
Loperamide	IBS-D Unselected patients with IBS	2 RCTs54,55	24 60	Placebo Placebo	Abdominal pain score 3.0 vs −0.14, P < .05 2.2 days with abdominal pain vs 8.3 days, P < .01
Eluxadoline, 100 mg or 75 mg b.i.d.	IBS-D	4 RCTs summarized in a meta-analysis56	2758	Placebo	RR of abdominal pain persistence = 0.89 (95% CI, 0.83–0.96) and 0.95 (95% CI, 0.88–1.04), respectively
Psyllium (up to 10 g/d)	Unselected patients with IBS	2 RCTs89,90	80 178	Placebo Placebo	Abdominal pain mild or absent in 52.5% vs 57.5%, N/S RR of adequate relief of abdominal pain at 1, 2, and 3 months = 1.60 (95% CI, 1.13–2.26), 1.44 (95% CI, 1.02–2.06), and 1.36 (95% CI, 0.90–2.04), respectively
Bran (up to 10 g/d)	Unselected patients with IBS	1 RCT90	190	Placebo	RR of adequate relief of abdominal pain at 1, 2, and 3 months = 1.13 (95% CI, 0.81–1.58), 1.22 (95% CI, 0.86–1.72), and 1.70 (95% CI, 1.12–2.57), respectively
Low FODMAP diet	IBS IBD	12 RCTs summarized in a meta-analysis91 2 RCTs92,93	914 52 89	BDA dietary advice Habitual diet Sham diet Sham diet Habitual diet	RR of abdominal pain persistence = 0.78 (95% CI, 0.57–1.06) RR of abdominal pain persistence = 0.72 (95% CI, 0.47–1.10) RR of abdominal pain persistence = 0.51 (95% CI, 0.30–0.87) Abdominal pain severity score 22 vs 30, P = .098 and 36 days with abdominal pain vs 38 days, P = .78 OR for improvement in abdominal pain frequency = 2.97 (95% CI, 1.12–7.89)
Rifaximin, 550 mg t.i.d. for 2 weeks	Nonconstipated IBS	2 RCTs summarized in a meta-analysis56	1260	Placebo	RR of abdominal pain persistence = 0.95 (95% CI, 0.89–1.01
FMT	IBS with bloating Unselected patients with IBS UC	2 RCTs96,97 1 RCT98	62 165 20	Placebo Placebo Usual treatment	Abdominal pain score 2.80 vs 3.88 at baseline with FMT, P = .001, compared with 3.57 vs 3.79 at baseline with usual treatment, P = .205 Abdominal pain score 166.8 and 186.3 posttreatment with 60 mg and 30 mg FMT, respectively, vs 307.0 with placebo, P < .001 Abdominal pain score 0.9 vs 4.5 at baseline with FMT, P = .026, compared with 1.8 vs 4.9 at baseline with usual treatment, N/S
Gelsectan	IBS-D	1 RCT99	60	Placebo	Number of patients with totally to slightly unacceptable abdominal pain reduced from 67% at baseline to 0% at 4 weeks with gelsectan vs 83% to 60% with placebo, statistical significance not reported
Probiotics Combination probiotics Lactobacillus-containing strains Saccharomyces cerevisiae I-3856 Bifidobacterium-containing strains Bacillus-containing strains	All in unselected patients with IBS	32 RCTs100 11 RCTs100 5 RCTs100 3 RCTs100 3 RCTs100	3469 1183 1482 389 212	Placebo Placebo Placebo Placebo Placebo	RR of abdominal pain persistence = 0.72 (95% CI, 0.64–0.82) RR of abdominal pain persistence = 0.59 (95% CI, 0.45–0.76) RR of abdominal pain persistence = 0.64 (95% CI, 0.45–0.90) RR of abdominal pain persistence = 0.78 (95% CI, 0.64–0.95) RR of abdominal pain persistence = 0.33 (95% CI, 0.23–0.47)
Ketotifen (titrated from 2 mg to 6 mg b.i.d.)	Unselected patients with IBS	1 RCT109	60	Placebo	7% of patients reporting severe abdominal pain vs 28%, P = .02
Ebastine 20 mg o.d.	Unselected patients with IBS Nonconstipated IBS	1 RCT110 1 RCT111	55 202	Placebo Placebo	Relief of abdominal pain in 41% vs 20%, P = .19 ≥30% improvement in abdominal pain in 37% vs 25%, P = .081
Disodium cromoglycate, 600 mg/d	IBS-D	1 RCT112	43	No treatment	≥50% improvement in abdominal pain in 77% vs 28%, P = .002
Peppermint oil (usually 2 capsules t.i.d.)	Unselected patients with IBS	7 RCTs summarized in a meta-analysis119	748	Placebo	RR of abdominal pain persistence = 0.76 (95% CI, 0.62–0.93)
Red pepper (capsaicin)	Unselected patients with IBS FD	1 RCT120 1 RCT121	50 30	Placebo Placebo	Abdominal pain score 1.9 vs 2.7 at baseline with red pepper, compared with 2.3 vs 2.4 at baseline with placebo, reported as “statistically significant” Abdominal pain score 1.61 posttreatment vs 2.37, P < .05
Alosetron, 1 mg b.i.d.	IBS-D	6 RCTs summarized in a meta-analysis56	2606	Placebo	RR of abdominal pain persistence = 0.83 (95% 0.78–0.88)
Ramosetron, 5 μg or 2.5 μg o.d.	IBS-D	5 RCTs summarized in a meta-analysis56	1928	Placebo	RR of abdominal pain persistence = 0.82 (95% CI, 0.75–0.89) and 0.75 (95% CI, 0.65–0.85), respectively
Ondansetron, 12 mg q.d, bimodal release or titrated up or down from 4 mg o.d.	IBS-D	3 RCTs summarized in a meta-analysis127	327	Placebo	RR of abdominal pain persistence = 0.95 (95% CI, 0.74–1.20)
Tegaserod, 6 mg b.i.d.	IBS-C FD	Pooled analysis of 4 RCTs128 2 RCTs129	2886 1360 1307	Placebo Placebo Placebo	OR for abdominal pain response = 1.38 (95% CI, 1.14–1.67) Abdominal pain response rate 44.9% vs 40.0%, P = .027 Abdominal pain response rate 44.0% vs 42.3%, P = .51
SSRIs (eg, escitalopram, 10 mg o.d.)	Unselected patients with IBS FD	5 RCTs summarized in a meta-analysis132 1 RCT133	262 195	Placebo Placebo	RR of abdominal pain persistence = 0.82 (95% CI, 0.58–1.16) Upper abdominal pain score 1.4 posttreatment vs 1.2, N/S
TCAs (eg, amitriptyline, 10–30 mg o.d., or imipramine, 50 mg o.d.)	Unselected patients with IBS FD	4 RCTs summarized in a meta-analysis132 1 RCT134 2 RCTs133,135	171 463 194 107	Placebo Placebo Placebo Placebo	RR of abdominal pain persistence = 0.53 (95% CI, 0.34–0.83) OR for ≥30% improvement in abdominal pain = 1.66 (95% CI, 1.12–2.46) Upper abdominal pain score 1.1 post-treatment vs 1.2, N/S Epigastric pain score 0.96 vs 1.24 at baseline with imipramine, P = .026, compared with 0.96 vs 1.13 at baseline with placebo, P = .13
SNRIs (eg., venlafaxine 150 mg o.d.)	Unselected patients with IBS	1 RCT136	30	Placebo	Frequency of abdominal pain or discomfort score 3.87 vs 4.93, P = .03
Oloroinab, 10 mg to 100 mg t.i.d.	IBS with abdominal pain Crohn’s disease with abdominal pain	1 RCT147 1 randomized, open-label study148	273 14	Placebo N/A	56.5%, 59.7%, and 56.7% of 10 mg, 25 mg, and 50 mg t.i.d., respectively, achieved a ≥30% improvement in abdominal pain vs 52.9% with placebo, N/S
					Change in abdominal pain score from baseline of −4.61 with 25 mg t.i.d. and −4.57 with 100 mg t.i.d.
Pregabalin, 75 mg o.d., or titrated up from 75 mg b.i.d.	Unselected patients with IBS FD	1 RCT154 1 RCT155	85 72	Placebo Placebo	Abdominal pain score 28 posttreatment vs 40, P = .008 Epigastric pain score 3.0 posttreatment vs 4.0, P = .01

Table 1

Summary of Evidence for Efficacy of Available Treatments Directed Against Peripheral Mechanisms of Abdominal Pain in Their Effect on Abdominal Pain as an End Point

BDA, British Dietetic Association; b.i.d., twice daily; CI, confidence interval; IBS-C, IBS with constipation; N/A, not applicable; N/S, not significant; o.d., once daily; OR, odds ratio; q.d., once daily; RR, relative risk; t.i.d., 3 times daily.

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Peripherally Acting Opioids and Visceral PainPharmacology and preclinical studies

Opioids signal through 4 GPCRs: μ-opioid receptors (MORs), δ-opioid receptors (DORs), κ-opioid receptors (KORs), and nociceptin opioid receptors.39 The analgesic effect of conventional opioids can be strong (eg, oxycodone, morphine) or weak (eg, codeine) and predominantly result from activation of MORs, although DORs and KORs also play a role. On nociceptors, these receptors trigger GPCR-Gi/o protein signaling leading to the recruitment of multifunctional intracellular proteins, called β-arrestins, and sustained signaling by endosomes.40 This signaling modulates ion channels and, ultimately, inhibits action potential firing. Receptor expression‎ is increased in inflammatory conditions, including active IBD, possibly leading to altered signaling.41

Conventional opioids can exhibit potent analgesic actions, particularly for acute pain, but are limited by their adverse effect profile, including cognitive impairment, respiratory depression, nausea, constipation, and addictive potential.42 Analgesic tolerance leads to dose escalation and consequently greater risk of these potentially life-threatening adverse effects. Dose escalation is also implicated in the development of a paradoxical switch in signaling, leading to opioid-induced hyperalgesia, a poorly understood condition.43 The opioid crisis has hastened the search for safer alternatives, including peripherally restricted opioids that lack addictive potential and central adverse effects such as respiratory depression and cognitive impairment.

Strategies to develop peripherally acting opioids are being explored to identify safe, yet effective, analgesics for visceral pain. Access to the central nervous system can be restricted, for example, by creating charged molecules, and several compounds display peripheral analgesic actions,44,45 including loperamide, a MOR agonist.46 To date, however, these do not exhibit sufficient analgesic effects to be clinically useful to treat visceral pain.

Another strategy is to target opioid receptor heterodimers, such as eluxadoline,47 a MOR agonist and DOR antagonist with weak affinity for KORs. MORs and DORs are coexpressed on nociceptors innervating the intestine, and eluxadoline shows high binding affinity for MOR/DOR heterodimers in cell assays48 and functional interaction between receptors. However, there has been sparse mechanistic study in whole-animal models to clarify the role of this interaction further.49

There are other promising strategies to develop safe opiates, such as enhancing endogenous opioids (eg, enkephalinase inhibitors), by developing pH-sensitive opioid analogues,50 which are only active at sites of inflammation and thus lack the adverse effect profile and addictive potential of conventional opioids. Combinations of subthreshold opioids and cannabinoid receptor 1 (CB1) agonists can provide strong analgesia51 without adverse effects. Novel delivery systems using nanoparticles of between 1 and 100 nm in diameter, containing opioid cargoes,52 target intracellular signaling in endosomes and can be delivered intrarectally to act locally within the inflamed colon. To date, most of these strategies are based on preclinical studies and none have been tested adequately in humans. Finally, female rodents are less sensitive to opiate analgesia,53 and whether these strategies have sex-specific effects would be important to eval‎uate.

Clinical trials

Few trials have been conducted with new opioid-related drugs in visceral pain, largely due to the negative impact of the opioid crisis. Despite widespread use of loperamide in clinical practice, there is little evidence for this. One 13-week RCT, recruiting patients with IBS with diarrhea (IBS-D), reported pain scores were significantly lower with loperamide.54 In a second 3-week trial that recruited IBS of all subtypes, the number of painful days was reduced significantly with loperamide, but only in patients with alternating bowel habit.55 Both trials used historical definitions of IBS, did not conform to guidance for design of treatment trials in DGBI, and many participants did not report abdominal pain at all. More rigorous trials of loperamide are needed, although it is unlikely these will ever be conducted.

In contrast, eluxadoline has been tested rigorously in phase III RCTs at 2 doses, 75 mg or 100 mg twice daily, with data pooled in a prior meta-analysis.56 Only 100 mg twice daily was superior to placebo for the FDA-recommended end point for abdominal pain, but benefit was modest. In addition, there have been safety issues, with episodes of acute pancreatitis and sphincter of Oddi dysfunction reported.

The Microbiome and Visceral PainAdvances in pathophysiology

The involvement of gut microbiota in the development of visceral pain is largely based on preclinical studies measuring pain thresholds after transfer of human stool microbiota into germ-free rodents or administration of live biotherapeutics (probiotics) or antibiotics, or both, in rodent models. For instance, germ-free rats colonized with stool microbiota from individuals with IBS display decreased pain thresholds in response to rectal distention.57 Further insights have been gained from studies involving gnotobiotic mice, revealing the role of commensal microbes in maintaining normal excitability of gut intrinsic neurons.58

Perturbing the gut microbiome during early life using vancomycin leads to visceral hypersensitivity in rats.59 Conversely, administration of live biotherapeutics, such as Faecalibacterium prausnitzii, Lactobacillus paracasei NCC2461, or Lactobacillus GG, reduces visceral hypersensitivity and intestinal permeability in preclinical models that alter the early-life microbiome.60,61 Unlike in early life, antibiotic administration improves visceral hypersensitivity in adult mice,62 suggesting potential age-dependent effects of the microbiome.

Interestingly, visceral pain responses to colorectal distention vary across the estrous cycle in female mice, but this effect is lost in germ-free animals. Ovariectomy caused visceral hypersensitivity in specific pathogen-free, but not germ-free mice, suggesting an interaction between sex hormones, visceral pain, and the microbiome.63

Building on insights from animal models, human studies exploring fecal microbiome changes in patients with IBS have found specific taxa that positively (Proteobacteria)64 or negatively (Bifidobacterium spp) correlate with the severity of pain.65 Although human microbiome studies have focused largely on the colon, changes in small-intestinal microbial composition, rather than bacterial numbers, appear to differentiate patients with abdominal pain from healthy controls.66 However, the role of small-intestinal microbiota in the pathophysiology of abdominal pain remains unclear. Together, although findings from preclinical models and human studies underscore a role of the gut microbiome, whether these changes are causal to the development of visceral hypersensitivity or a consequence of changes in diet and gastrointestinal motility is unknown.

Gut microbiota-derived metabolites, neurotransmitters, toxins, and cell wall components have emerged as potential factors underlying the pathophysiology of visceral hypersensitivity. These bioactive compounds can (1) sensitize sensory neurons indirectly by stimulating either enteroendocrine cells, which release serotonin, or immune cells, which release chemokines and cytokines, both of which act on distinct neuronal populations, (2) disrupt the intestinal barrier, allowing passage of potentially noxious stimuli, and (3) activate sensory neurons directly, particularly in instances where barrier function is compromised (Figure 2). Most bacteria-derived compounds are pleiotropic, acting via multiple signaling pathways. Thus, they exert wide-ranging effects. Furthermore, gut microbiota can both synthesize and use neurotransmitters, encompassing excitatory, such as glutamate, histamine, dopamine, and norepinephrine, and inhibitory neurotransmitters, such as γ-aminobutyric acid (GABA).67 These neurotransmitters allow intercommunication among microbiota members and the host.

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Figure 2 Mechanisms underlying gut microbiome-driven visceral nociception. Gut microbiome-derived products can sensitize peripheral nociceptors directly or act indirectly by stimulating immune cells or enterochromaffin cells, or both, to release cytokines, chemokines, or serotonin, or a combination of these, respectively. The gut microbiome can also modulate intestinal barrier function by altering the luminal bile acid and protease pool or through metabolites such as butyrate. AHR, aryl hydrocarbon receptor; CA, carboxylic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; FFAR, free fatty acid receptor; FXR, farnesoid X receptor; GPR35, G protein-coupled receptor 35; LCA, lithocholic acid; LPS, lipopolysaccharide; LTS, leukotrienes PAMPs, pathogen-associated molecular patterns; PAR2, protease activated receptor 2; PGN, peptidoglycan; TGR5, Takeda G protein-coupled receptor 5; TLR, Toll-like receptor.

Enterochromaffin cells are the primary cell type responsible for peripheral serotonin production. They are polymodal chemosensors, capable of detecting specific luminal signals via an array of receptor pathways and translating them to the enteric nervous system by modulating serotonin-sensitive primary afferent nerves.68 Catecholamine neurotransmitters, such as norepinephrine and dopamine, initiate the adrenoceptor alpha 2A (Adrα2A) and the transient receptor potential cation channel subfamily C member 4 (TRPC4) signaling cascade.

On the other hand, short-chain fatty acids (SCFAs) and branched-chain fatty acids, such as isovaleric acid and, to a lesser extent, butyrate, activate the olfactory receptor 558 and P/Q type Cav channel within enterochromaffin cells.68 A multitude of bacterial metabolites, including butyrate, also augment serotonin synthesis within enterochromaffin cells.69 The role played by serotonin in modulating visceral pain, as well as the critical role of enterochromaffin cells in isovalerate-induced visceral hypersensitivity, is discussed further below.

Pathogen-associated molecular pattern molecules, which include bacterial cell wall components such as lipopolysaccharide, bind to pattern recognition receptors such as Toll-like receptors, are present on immune cells and sensory neurons. Pathogen-associated molecular pattern molecules contribute to visceral hypersensitivity by influencing nociceptors directly or by affecting immune cells indirectly, leading to peripheral sensitization.70,71 Diet-derived metabolites from bacterial fermentation, such as SCFAs, indole and indole derivatives, and kynurenine, also modulate visceral nociception. Butyrate exerts antinociceptive effects72 via peroxisome proliferator-activated receptors suppressing the activity of nuclear factor κ-light-chain-enhancer of activated B cells, involved in pain and inflammation.73,74

Butyrate also augments intestinal barrier function via activation of hypoxia inducible factor,75 regulates immune cells via free fatty acid 2/3 receptors,76 and drives epigenetic changes. Tryptophan is converted by microbes to kynurenic acid77 or to indole derivatives,78 both of which exert anti-inflammatory effects via G protein-coupled receptor 35 and aryl hydrocarbon receptor, respectively,79,80

Gut bacteria play an important role in determining the luminal bile acid and protease pool. Bile acid metabolites, including deoxycholic acid, regulate pain through the activation of G protein-coupled bile acid receptor 1, and are present in both primary sensory neurons and macrophages. Proteases contribute to visceral hypersensitivity by targeting intestinal barrier function81 as well as by signaling directly through protease activated receptor 2, present on neurons.82 The luminal protease pool depends on the balance between bacterial proteases83 and suppression of host proteases by bacteria harboring β-glucuronidases.81

The identification of distinct microbiota-driven mechanisms opens the door for novel therapeutic strategies. Currently, microbiota-targeted interventions largely focus on augmenting intestinal barrier function. In preclinical studies, fiber maintained both microbial diversity and barrier function,84 and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) was found to preserve barrier function by decreasing lipopolysaccharide-mediated mast cell activation.85

Clinical trials

There are a multitude of methods to manipulate the microbiome, and thereby microbial metabolites, as a means of treating abdominal pain. SCFA enemas have been studied in IBD, but trials have not reported an effect on abdominal pain.86–88 Fiber has been assessed in IBS, but few trials report abdominal pain outcomes.89,90 One 12-week RCT found there was no benefit of psyllium, a soluble fiber, over placebo,89 but in another trial of psyllium, bran, or placebo, significant improvements in abdominal pain occurred with both psyllium and bran at several time points.90

A network meta-analysis of 12 trials studied the effect of a low FODMAP diet on abdominal pain.91 It was superior to a sham diet but was not superior to standard British Dietetic Association dietary advice for IBS or habitual diet. In contrast, in a RCT comparing a 4-week low FODMAP diet with a sham diet in patients with quiescent IBD with persistent gastrointestinal symptoms, abdominal pain severity and days with abdominal pain did not differ.92 In another 6-week trial of a low FODMAP diet vs normal diet in patients with IBD in remission with ongoing gastrointestinal symptoms, response for abdominal pain frequency, but not severity, was significantly higher with the low FODMAP diet.93 Abdominal pain response rates with rifaximin, a minimally absorbed antibiotic, according to the FDA-recommended end point, were reported in a meta-analysis.56 There was no benefit with rifaximin over placebo.

Although there have been multiple RCTs of fecal microbial transplant (FMT) in both IBS and IBD, summarized in prior meta-analyses,94,95 few report impact of FMT on abdominal pain. Two RCTs of FMT in IBS studied this end point.96,97 One 12-week trial of a single FMT via nasojejunal tube in IBS with predominant bloating reported abdominal pain scores were significantly reduced.96 In the second RCT, 30 mg or 60 mg of a single FMT via gastroscopy led to a significant reduction in abdominal pain at 3 months vs placebo.97 One RCT comparing FMT with usual therapy in active ulcerative colitis reported abdominal pain scores improved significantly with FMT at 2 weeks compared with baseline, but also improved significantly in the usual therapy arm.98

Gelsectan, a prebiotic with mucoprotective and bifidogenic effects, which may reinforce the intestinal barrier, was studied in 1 crossover trial.99 The number of participants with totally to slightly unacceptable abdominal pain was reduced from baseline to 4 weeks compared with placebo. Finally, in a meta-analysis certain combinations of probiotics, Lactobacillus-containing strains, Saccharomyces cerevisiae I-3856, and Bifidobacteria- and Bacillus-containing strains improved abdominal pain, but certainty in the evidence was low to very low across the studies, with heterogeneity between individual trials in most analyses.100

Histamine and Visceral PainPharmacology and preclinical studies

Histamine functions as a paracrine signaling molecule that can activate nociceptors in the gastrointestinal tract (Figure 3). It is a member of the biogenic amine family and is synthesized from l-histidine exclusively by l-histidine decarboxylase.101 Histamine signaling to nociceptors in the gut could originate from 2 sources: intestinal tissue or the lumen. In tissue, it is stored in high concentrations, predominantly in mast cells, but also in basophils and eosinophils. However, other cells in the gut also express histidine decarboxylase, including macrophages, neutrophils, platelets, and dendritic cells, and can synthesize and release histamine but do not store it.102 In the lumen of the gastrointestinal tract, there are 3 possible sources: synthesis by microbiota, ingestion of histamine-rich foods, and histamine released from tissues that permeates into the lumen.

Figure viewer

Figure 3 Novel mechanisms causing increased histamine signaling to intestinal nociceptors. (A) This schema shows that after combined food antigen (red triangle) and acute self-limiting colitis or combined food antigen and psychological stress exposure, reexposure to food antigen alone triggers increased IgE release within the intestine (which is not systemic), causing mast cell degranulation within the intestinal wall. The ensuing histamine release causes nociceptor sensitization and increased pain signaling. (B) This schema shows that ingestion of poorly absorbed complex carbohydrates (CHO) (eg, FODMAPs) can stimulate microbial production of histamine. Patients with Klebsiella aerogenes produce up to 100 times more histamine than those lacking this bacterium in their stool samples. Luminal histamine stimulates H4 and H1 receptors, leading to mast cell degranulation with ensuing nociceptor sensitization and increased pain signaling. DRG, dorsal root ganglia.

Histamine is metabolized by 2 dominant pathways, histamine-N-methyltransferase and diamine oxidase,103 resulting in N-methyl histamine and imidazole acetaldehyde metabolites, respectively. These metabolites also exhibit biological activity (eg, N-methyl histamine), and the preponderance of the pathways may differ between mast cells and microbiota.

Histamine, and possibly some metabolites, can activate 4 GPCRs, H1 to H4.101 These GPCRs signal intracellularly via Gq and cyclic adenosine monophosphate to modulate passive and voltage-gated ion channels on nociceptors and other effector pathways in nonneuronal cells. The distribution of these receptors within the gut suggests histamine activates pain signaling directly through activation of neurons and indirectly via immune cell activation (Figure 3).

In humans,104 H1 receptors are found on connective tissues cells, immune cells, enterocytes, smooth muscle cells, and nerves, H2 receptors are found on gastric parietal cells, enterocytes, immunocytes, enteric nerves, and smooth muscle cells, and H4 receptors are expressed on immune cells, blood vessels, nerves, and enterocytes. H3 receptors have yet to be identified in humans.

Previous studies highlight the role of histamine in patients with IBS, demonstrating increased levels of histamine (and proteases) in mucosal biopsy specimens from patients compared with healthy controls, evidence of mast cell activation, and the ability of histamine in tissue supernatants from patients to exaggerate activation of rodent and human nociceptive neurons.105 Sex differences have not been described. More recent studies show increases in duodenal eosinophils in patients with FD, another source of tissue histamine, implicating a role in abdominal pain in this disorder.106 The triggers resulting in abnormal mast cell-histamine signaling observed in these patients have been unclear, but recent preclinical studies suggest multiple possible etiologies, as outlined below.

When mice develop a self-limiting bacterial colitis and are exposed simultaneously to a food antigen, and then reexposed to the food antigen alone after resolution of infection, they lose oral tolerance to the food antigen.14 This leads to visceral hypersensitivity and mast cell activation with histamine release. This exaggerated pain signaling was blocked by an H1 receptor antagonist, which inhibits histamine signaling to neurons, and by an IgE antibody, which prevents mast cell activation. Tissues exhibited elevated IgE levels, consistent with loss of oral tolerance, but there was no systemic increase in IgE, highlighting immune activation was confined to the intestine.

Injection of common antigens into the rectal mucosa in patients with IBS caused greater wheal and flare responses, compared with healthy volunteers, consistent with the hypothesis that some patients with IBS are sensitized to food antigens.14 Recent preliminary studies suggest psychological stress can also induce loss of oral tolerance to food antigens and lead to mast cell-histamine–mediated visceral hypersensitivity in both the small intestine and colon, a feature observed in many patients with IBS.107

Histamine production by the microbiota may be stimulated by poorly absorbed complex carbohydrates. In a study using germ-free mice to create a humanized IBS mouse model with fecal microbiota from patients with IBS and healthy controls,108 mice given fecal samples from patients with IBS who were high histamine producers, based on stool and urine samples, exhibited visceral hyperalgesia. This exaggerated pain signaling was blocked by H1- and H4- receptor antagonists, suggesting several signaling pathways were involved (Figure 3). Some of the histamine in the luminal samples could originate from the host (eg, mast cell degranulation). However, high histamine producers were found to have microbial species, including Klebsiella aerogenes, in their stool that could make up to 100 times more histamine than those without.

Clinical trials

Drugs targeting histamine receptors or stabilizing mast cells have not been well studied in gastrointestinal diseases. An 8-week trial of ketotifen, a H1-receptor antagonist, in IBS reported a significant improvement in abdominal pain over placebo.109 Ebastine, another H1-receptor antagonist, has been assessed in IBS.110,111 A 12-week proof-of-concept RCT found rates of relief of abdominal pain were numerically higher with ebastine, but not significantly so. In a subsequent phase IIb placebo-controlled trial, rates of abdominal pain improvement were higher with ebastine, although this was not significant.111 The effect of the mast cell stabilizer disodium cromoglycate on abdominal pain was studied in a RCT in IBS-D.112 In this 6-month study, compared with no treatment, significantly more patients randomized to disodium cromoglycate experienced abdominal pain improvement.

Transient Receptor Potential Vanilloid 1 and Visceral PainPharmacology and preclinical studies

TRPV1 is a nxxxxonselective ligand-gated cation channel that is highly enriched in gastrointestinal tract nociceptors. It is activated by polymodal stimuli, including mechanical stretch, noxious heat, low pH, exogenous chemical irritants, such as capsaicin (the active ingredient in chili peppers), and endogenous lipid metabolites of arachidonic acid (eg, the endocannabinoid anandamide113). Selective ablation of colon-projecting TRPV1-expressing neurons decreased nociception in response to colorectal distention in mice,22 highlighting its critical role in visceral pain. Estrogens can modulate lumbosacral dorsal root ganglia TRPV1 expression‎, suggesting a potential mechanism for sex differences in visceral pain.114

Sensitization of TRPV1 by inflammatory mediators, such as histamine,110 is one of the key pathways in mediating peripheral visceral hypersensitivity, as discussed above. However, TRPV1 expression‎ does not necessarily correlate with receptor sensitization. For example, in patients with IBS who were hypersensitive to rectal distention, rectal application of capsaicin caused increased pain perception. No change in TRPV1 expression‎ was noted when comparing hypersensitive and normosensitive patients with IBS, suggesting that although TRPV1 expression‎ is important, additional factors, such as receptor sensitization or central factors, or both, are necessary in mediating visceral pain.115

Although most of the studies have focused on TRPV1 sensitization in IBS and FD,113 TRPV1 may also play a role in chronic visceral pain in patients with IBD in remission. Rectal TRPV1 expression‎ was increased in patients with IBD in endoscopic remission with chronic visceral pain and correlated with patient-reported symptoms.116 Visceral hyperalgesia was TRPV1-dependent in postinflammatory mice,117 and they also displayed increased SCFA-producing microbiota and stool SCFA content. These microbial-derived SCFAs increased capsaicin-evoked calcium responses in the postinflammatory state, suggesting that microbial metabolites can sensitize TRPV1.118

Clinical trials

Peppermint oil, as well as being a smooth muscle relaxant, may have effects on TRPV1 signaling. A meta-analysis showed it was more efficacious than placebo for abdominal pain.119 However, benefit was modest, with heterogeneity between studies, and most trials did not use FDA-recommended end points. Although capsaicin stimulates the TRPV1 receptor, leading to worsening abdominal pain, repeated administration down-regulates the receptor. A 6-week trial in IBS showed abdominal pain scores were significantly lower, compared with baseline, in patients receiving red pepper pills compared with those receiving placebo.120 A similar 5-week study in FD demonstrated a significant reduction in epigastric pain scores with red pepper vs placebo.121 However, patients in both trials randomized to red pepper dropped out due to pain exacerbations.

Serotonin (5-Hydroxytryptamine) and Visceral PainPharmacology and preclinical studies

The monoamine neurotransmitter 5-hydroxytryptamine (5HT) plays an integral role in initiation of intrinsic gut reflexes regulating motility, secretion, and vasodilation. It also participates in the pathogenesis of visceral pain via afferent nerve 5-HT3 and 5-HT4 receptors; drugs that modulate these receptors have been used extensively in the treatment of visceral hypersensitivity.122 The actions of 5HT are terminated by the serotonin selective reuptake transporter, a peripheral target of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and serotonin norepinephrine reuptake inhibitors122 (SNRIs).

Genetic polymorphisms in the 5-HT3 receptor and the serotonergic synthetic enzyme, tryptophan hydroxylase, are associated with increased IBS susceptibility, whereas SSRI transporter polymorphisms are associated with both IBS and FD.123 Multiple studies report changes in 5HT synthesis, reuptake, and release in IBS,124 suggesting dysregulated 5HT signaling contributes to the pathophysiology of visceral pain. Surprisingly, few studies eval‎uating the role of TCAs in visceral pain have been performed in rodent models.

Although 5HT can be secreted by enteric neurons and mucosal mast cells, most of the body’s 5HT is synthesized and stored by enterochromaffin cells.122 Enterochromaffin cells are electrically excitable, and display axon-like basal processes, forming functional connections with extrinsic and intrinsic afferent neurons, termed neuropods.68,125 Enterochromaffin cells function as luminal sensory transducers, releasing 5HT in response to dietary nutrients and microbial products, as well as mucosal distortion via mechanosensitive Piezo-02 channels.126 5HT release by enterochromaffin cells, thus initiates intrinsic gut reflexes and stimulates extrinsic nerves.

A recent study eval‎uated the role of a mucosal afferent-enterochromaffin cell circuit in the pathogenesis of visceral hypersensitivity using transgenic mice,26 where enterochromaffin cells could be activated or silenced selectively. Direct activation of enterochromaffin cells elicited 5HT release and was sufficient to cause both acute and chronic visceral hypersensitivity to colorectal distention. Remarkably, activation of enterochromaffin cells was sufficient to elicit anxiety-like behavior in mice. These effects were inhibited by the 5HT3 antagonist alosetron, which decreased mucosal afferent activity. Conversely, silencing activity of enterochromaffin cells attenuated 5HT release and visceral hypersensitivity mediated by the microbial metabolite, isovalerate, in male mice. The mucosal afferent-enterochromaffin cell circuit demonstrated high tonic activity in female, but not male, mice suggesting a sex-specific contribution to pain signaling. Together, these data demonstrate that the enterochromaffin cell-mucosal afferent circuit plays an essential role in pathogenesis of visceral hypersensitivity.26

It is possible that the GC-C pathway also regulates 5HT secretion from enterochromaffin cells. GC-C is expressed not only by enterocytes but also by a subtype of monoamine synthesis-expressing neuropods enriched in the proximal intestine of mice.36 GC-C enriched neuropods formed functional connections with nociceptors in cocultures and caused spontaneous nociceptor activation, which was abolished by linaclotide. The antinociceptive effects of linaclotide on the response to colorectal distention were lost in mice that were deficient in neuropod GC-C.36 Thus, it is possible that enterochromaffin GC-C activation regulates 5HT tone, but whether this mechanism is active in vivo is unclear.

Clinical trials

The efficacy of the 5HT3-receptor antagonists alosetron and ramosetron, according to the FDA-recommended end point for abdominal pain, has been reported in multiple trials in IBS-D, pooled in a meta-analysis.56 Ramosetron, 2.5 μg daily and 5 μm daily, and alosetron, 1 mg twice daily, were superior to placebo, although alosetron has been associated with ischemic colitis. Varying doses of ondansetron, another 5HT3-receptor antagonist with a long history of safety, were assessed in 3 trials in IBS-D, summarized in another meta-analysis.127 The drug was not superior to placebo for pain.

For 5HT4-receptor agonists, in a pooled analysis of data from 4 RCTs in IBS, tegaserod, 6 mg twice daily, was more efficacious for pain than placebo.128 In two 6-week trials of tegaserod in FD, 6 mg twice daily was superior to placebo for abdominal pain in 1 RCT but not the other.129 Safety issues arising from cardiovascular and cerebrovascular ischemic events led to the withdrawal of tegaserod. Although it was reintroduced briefly, tegaserod is now no longer available. Prucalopride was assessed in chronic constipation and was efficacious,130 but no RCTs report its efficacy in improving abdominal pain, and it has never been tested in IBS or FD.

Although SSRIs, TCAs, and SNRIs are antidepressants, in the context of treating abdominal pain, they act as gut-brain neuromodulators involving, at least in part, 5-HT131; discussion of the central actions of these compounds is beyond the scope of this review. SSRIs have been assessed in IBS and FD, with no impact on abdominal pain in IBS in a prior meta-analysis,132 and a reduction in pain scores in FD in a single RCT of escitalopram, 10 mg once daily, but with no benefit over placebo.133 TCAs, however, were more efficacious than placebo for abdominal pain in IBS in a meta-analysis of 4 RCTs132 and more recently in a 6-month trial in 463 patients.134 In one 12-week trial in refractory FD, imipramine led to a significant reduction in epigastric pain scores vs placebo,135 but another trial of amitriptyline demonstrated no benefit.133 The SNRI venlafaxine was assessed in a single 12-week RCT in IBS; abdominal pain frequency scores were reduced significantly compared with placebo.136 An RCT of FD did not report its effect on abdominal pain.137

Cannabinoids and Visceral PainPharmacology and preclinical studies

Cannabinoids are widely used alternative therapies to treat abdominal pain in both IBD and IBS.138,139 The actions of cannabinoids are mediated via the endocannabinoid system, which regulates gastrointestinal motility, secretion, immune function, intestinal permeability, and visceral hypersensitivity.140

The classical components of the endocannabinoid system are the endogenous cannabinoid ligands, anandamide, and 2-arachidonoylglycerol, as well as their biosynthetic and degradative enzymes. These are found throughout the microbiota-gut-brain axis, including the epithelium, enterochromaffin cells, enteric nervous system, and immune system, as well as extrinsic afferent nerves, where they primarily exert an antinociceptive effect. Anandamide is also an agonist at TRPV1. Thus, endocannabinoids have both pronociceptive and antinociceptive effects, depending on the receptor.140 Interestingly, commensal bacteria can produce endocannabinoid-like molecules,141 although whether a microbial source of endocannabinoid-like molecules plays a role in visceral hypersensitivity is unknown.

In animal models of stress-induced visceral hypersensitivity and in postinflammatory models, CB1 and CB2 agonists decrease the visceromotor response to colorectal distention.140,142–144 Endocannabinoids can either exert their antinociceptive actions directly via CB1 and CB2 receptors expressed on nociceptors142,145 or indirectly via down-regulation of mast cell or macrophage activation.140 However, clinical use of cannabinoids is hampered by psychotropic adverse effects. Accordingly, there has been interest in synthesizing peripherally restricted cannabinoid receptor agonists.142–144

A recent preclinical study of the peripherally restricted CB2 receptor agonist, olorinab, was performed in rodent models of acute colitis and postinflammatory visceral pain.142 Olorinab reversed the colitis-induced hypersensitivity to colorectal distention in both the acute and postinflammatory state; no effects on visceral pain were seen when olorinab was given to controls. Olorinab was able to decrease mechanosensitivity of ex vivo afferent nerves in a dose-dependent manner, both in acute colitis and in the postinflammatory state, although CB2 expression‎ was not up-regulated in afferent nerves compared with controls.142 Unfortunately, only male mice were eval‎uated in this study, although CB2 expression‎ is increased in female patients with IBS.146 These data suggest CB2 receptors on visceral afferents are sensitized by inflammation and, in turn, play a regulatory anti-nociceptive role.

Clinical trials

In a 12-week phase II dose-ranging study of olorinab in IBS, the proportion of patients experiencing improvement in abdominal pain was not significantly higher with any dose studied.147 However, in those with moderate to severe pain at baseline, abdominal pain scores were significantly improved with 50 mg 3 times daily. No placebo-controlled trials of this drug in IBD have been conducted, although an 8-week open-label randomized study recruiting patients with Crohn’s disease who reported abdominal pain found a significant reduction in pain scores from baseline with olorinab.148 There is no evidence for other drugs acting on cannabinoid receptors for treating abdominal pain in gastrointestinal disorders.149

γ-Aminobutyric Acid and Visceral PainPharmacology and preclinical studies

Functional GABA receptors have been identified in the nerve terminals of colonic afferents. The activation of GABA receptors (GABAA and GABAB) by endogenous GABA decreases sensitivity of colonic afferents, whereas GABAA activation also reduces visceral pain perception.150 Functional GABAergic transmission has also been found in nociceptors, producing strong analgesic effects.151 In addition to endogenous production, certain bacteria expressing glutamate decarboxylase, can produce GABA from glutamate.67 In rodent models, GABA-producing bacteria have an analgesic effect in stress-induced152 and fecal-retention153 models of visceral hypersensitivity.

Clinical trials

There has been 1 RCT of pregabalin in both FD and IBS, but no trials in other painful gastrointestinal disorders and no trials of gabapentin. Abdominal pain scores were significantly lower in patients assigned to titrated pregabalin vs placebo in a 12-week trial in IBS.154 Similarly, pregabalin, 75 mg daily, was superior to placebo for epigastric pain scores in an 8-week trial in FD.155

Conclusions

Chronic visceral pain represents a substantial burden to patients. Despite the potential for the evidence-based treatments described above, a need remains for the development of novel therapeutics to treat sensitization of peripheral pain pathways effectively. Future directions should include the identification of microbial vs host sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), similar to current work eval‎uating histamine (Figure 4).

Figure viewer

Figure 4 Areas for future investigation in peripheral mechanisms of visceral pain. There is a need to identify peripheral mechanisms underlying visceral pain and develop novel therapeutic agents to treat patients. Identification of microbial vs host sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), is one such mechanistic area. Eval‎uation of the relative contribution of each pathophysiologic mechanism to nociceptor sensitization in individual patients, and thus use of combination therapies targeting these mechanisms, is key. For opiates, some promising strategies for the development of safe yet effective opiate therapies are the development of pH-sensitive opiate analogues active at the site of inflammation, use of peripherally restricted agents or subthreshold combinations of opiates, and CB1 receptor agonists. Because chronic visceral pain is more common in women, future studies should eval‎uate whether pain mechanisms are sex-specific and whether treatments should be used in a sex-specific manner. ♀, female; ♂, male.

With respect to the microbiome, research should avoid observational-based community profiling and focus on mechanistic approaches eval‎uating how microbiota or microbial products, or both, interact with nociceptors. Methods to test the relative contribution of each pathophysiologic mechanism to the sensitization of peripheral nociceptors and their role in overlapping pain syndromes in individual patients is also required. This would allow the use of specific drug combinations to target multiple mechanisms synergistically.

Given the sex bias of chronic visceral pain, future studies should eval‎uate whether pain mechanisms are sex-specific or whether treatments should be used in a sex-specific manner. Identifying whether differing or similar peripheral mechanisms are involved in the development of chronic visceral pain in patients with IBD vs painful DGBI will be important. Finally, eval‎uation of the relative contribution of peripheral vs central sensitization to symptoms would be important to individualize patient therapy. Continued multidisciplinary collaboration between clinician-scientists and bench-based scientists with the use of innovative reverse translational approaches is necessary to advance this field, identify new target pathways, and improve the clinical management of patients.

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Reviews in Basic and Clinical Gastroenterology and HepatologyVolume 166, Issue 6p976-994June 2024Open access

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Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments

Alexander C. Ford1,2,∗ ∙ Stephen Vanner3,∗ ∙ Purna C. Kashyap4 ∙ Yasmin Nasser5 ynasser@ucalgary.ca

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Abstract

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

Keywords

1. Visceral Pain
2. Inflammatory Bowel Disease
3. Irritable Bowel Syndrome
4. Histamine
5. Serotonin
6. Microbiome
7. Abdominal Pain
8. Inflammation

Abbreviations used in this paper

1. HT (5-hydroxytryptamine)
2. CB1 (cannabinoid receptor 1)
3. cGMP (guanosine 3′,5′-cyclic monophosphate)
4. DGBI (disorders of gut-brain interaction)
5. DOR (δ-opioid receptor)
6. FD (functional dyspepsia)
7. FDA (Food and Drug Administration)
8. FMT (fecal microbial transplant)
9. FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols)
10. GABA (γ-aminobutyric acid)
11. GC-C (guanylate cyclase-C)
12. GPCRs (G protein-coupled receptors)
13. IBD (inflammatory bowel disease)
14. IBS (irritable bowel syndrome)
15. IBS-D (inflammatory bowel disease with diarrhea)
16. KOR (κ-opioid receptor)
17. MOR (μ-opioid receptor)
18. RCT (randomized controlled trial)
19. SCFA (short-chain fatty acid)
20. SNRI (serotonin norepinephrine reuptake inhibitor)
21. SSRI (selective serotonin reuptake inhibitor)
22. TCA (tricyclic antidepressant)
23. TRP (transient receptor potential)
24. TRPV1 (transient receptor potential vanilloid 1)
25. US (United States)

Pain, defined as an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage, can be acute or chronic.1 It can originate from somatic (muscle, bone, or soft tissue) or visceral (thoracic, abdominal, or pelvic organs) structures.1 Visceral pain is one of the most challenging clinical conditions facing patients and their health care providers. It is extremely common. Abdominal pain is a key reason that patients with gastrointestinal disorders, such as inflammatory bowel disease (IBD) or disorders of gut-brain interaction (DGBI), including irritable bowel syndrome (IBS) or functional dyspepsia (FD), seek medical attention.2,3 More than 70% of patients with IBD experience abdominal pain during an acute flare,4 and between 20% and 60% report chronic abdominal pain.5 Chronic visceral pain is a hallmark of some DGBI, which affect up to 40% of adults, primarily women, worldwide.6

The diagnosis and treatment of chronic visceral pain is difficult, largely because it is poorly localized and difficult to describe due to the relatively small density of nerve terminals in the viscera and the divergent projections into the spinal cord,7 and because the pathophysiology remains incompletely understood. Chronic visceral pain is, thus, a significant burden to patients and is associated with anxiety, depression, decreased quality of life, and increased direct and indirect health care costs.5,8,9 IBS alone is estimated to cost the United States (US) ∼US $350 million each year for outpatient clinic visits, not including diagnostic testing, medications, nonpharmacologic therapies, or indirect costs due to lost productivity.10 Unfortunately, these challenges have been further amplified by the opioid crises.11,12 This highlights the continued need for advances in understanding of the pathophysiology of visceral pain to enable both effective and safe therapies.

Chronic visceral pain is a disorder of the microbiota-gut-brain axis, and central and peripheral mechanisms both contribute to its pathogenesis (Figure 1). Triggers include stress, psychological comorbidities, such as anxiety or depression, diet, low-grade intestinal inflammation, and microbial dysbiosis.4,13–15 Most abdominal pain signaling originates from nociceptors (pain-sensitive neurons), called visceral primary afferent nerves, whose cell bodies lie in the dorsal root ganglia and which have pseudo-unipolar axons connecting the intestine and the spinal cord.16 Nociceptors synapse with second-order neurons in the thoracolumbar and lumbosacral spinal cord17 and thereafter with central ascending pain pathways. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways originating from the hypothalamus and midbrain.18

Figure viewer

Figure 1 Chronic visceral pain is a disorder of the gut-brain axis. Nociceptors have cell bodies that lie in the dorsal root ganglia (DRG) and pseudounipolar axons that connect the intestine and the spinal cord. These synapse with second-order neurons in the spinal cord and with central ascending pathways thereafter. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways. (Inset) At the level of the mucosa, nociceptive terminals are both mechanosensitive and chemosensitive and are stimulated by luminal factors (eg, microbial products and nutrients) as well as by host mediators released due to infection, inflammation, or tissue damage (eg, serotonin, histamine, proteases, chemokines, and cytokines). These mediators can act indirectly via the epithelium/enterochromaffin cells or can stimulate nociceptors directly if there is a breakdown in the mucosal barrier. This results in sensitization of ion channels such as TRP, resulting in increased visceral pain.

Sensitization of nociceptors, defined as a decrease in the threshold for stimulation and an increase in the magnitude of the response,19 can occur peripherally, in the central nervous system, or both. This results in hyperalgesia, a heightened response to painful stimuli, and allodynia, which is pain arising from nonpainful stimuli.19 Central sensitization may also result in comorbid pain involving different organ systems,20 a discussion of which is beyond the scope of this review.

At the level of the periphery, nociceptive nerve terminals are found in muscle and serosa as well as in the mucosa.7 Nociceptors are mechanosensitive and are stimulated by stretch or distention.16 These actions are mediated by a variety of mechanosensitive ion channels, such as the transient receptor potential (TRP) receptors, including TRP vanilloid 1 (TRPV1) and 4, and TRP ankyrin 1, the 2-pore domain potassium channel family, the degenerin/epithelial sodium channel family, including the acid-sensing ion channels 1, 2, and 3, and the piezo-type mechanosensitive ion channel component 2 (Piezo-02).21,22

Nociceptors at the mucosal level are also chemosensitive and are stimulated by luminal factors, such as microbial products and nutrients, as well as by chemical mediators released during tissue infection, inflammation, or damage. These include bacterial toxins, neurotransmitters, proteases, bioactive amines, such as histamine, and serotonin, neurotrophins, adenosine-5′-triphosphate, chemokines, and cytokines (Figure 1, inset).13,23 Luminal products can either stimulate nociceptors directly, particularly if there is associated breakdown in the mucosal barrier as seen in both IBD and IBS,24,25 or indirectly via the epithelium or enteroendocrine cells.26

Chemical compounds and luminal products can, in turn, stimulate pronociceptive G protein-coupled receptors (GPCRs) or lead to increased expression‎ and activation of ion channels, such as TRP or voltage-gated sodium and calcium channels, or can decrease potassium channel activation and expression‎, resulting in peripheral sensitization. In turn, nociceptors can release neurotransmitters, such as substance P and calcitonin gene-related peptide, which augment the inflammatory response in the periphery and activate second-order neurons in the spinal cord, leading to neurogenic inflammation13,23 (Figure 1, inset).

Building on this pathophysiological framework, this review will focus on recent advances in visceral peripheral pain neurotransmission and mechanisms that result in sensitization of afferents in patients with IBD or painful DGBI. It will discuss specific physiologic and pathophysiologic preclinical peripheral mechanisms that have been translated into receptor-based treatment approaches for visceral pain in clinical trials. Some of these treatments have targeted advances in the physiology of nociceptors or intermediary cells, or both, whereas others target new understanding of pathophysiologic mechanisms of specific disorders.

Mechanistic Advances and the Resulting TherapiesGuanylate Cyclase-C and Visceral PainGuanylate cyclase-C pharmacology and preclinical studies

The enterocyte receptor guanylate cyclase-C (GC-C) plays an essential role in fluid secretion, barrier function, and nociception. Drugs such as linaclotide and plecanatide have taken advantage of this homeostatic system to treat visceral pain. GC-C is found on the apical surface of enterocytes throughout the gastrointestinal tract and is activated by the paracrine hormones uroguanylin and guanylin.27 Activation of GC-C triggers enzymatic conversion of guanosine-5ʹ-triphosphate to guanosine 3′,5′-cyclic monophosphate (cGMP), which in turn regulates activity of the apical cystic fibrosis transmembrane conductance regulator, leading to increased luminal chloride and bicarbonate secretion and a secondary increase in intestinal motility.27 Genetic mutations in the guanylate cyclase 2C gene (GUCY2C) have been found in patients with congenital secretory diarrhea28 and may predispose patients to IBD,29 whereas dysregulated GC-C expression‎ has been implicated in the pathophysiology of both IBD30 and IBS.31 Sex differences have not been reported.32

Epithelial GC-C signaling has a key role in nociception. Linaclotide, a minimally absorbed GC-C agonist, decreased the visceral motor response to colorectal distention in both acute colitis and stress-induced models of visceral hypersensitivity. The effects of linaclotide were abolished in GC-C–knockout animals, confirm‎ing its specificity.33 Linaclotide34 or direct application of cGMP34,35 to an ex vivo preparation of nociceptor afferents decreased response to circumferential stretch in control animals as well as in acute colitis35 and in postinflammatory34 models of visceral pain. GC-C expression‎ was not found on nociceptors,34,35 suggesting its antinociceptive effects were indirect. Indeed, linaclotide34 and uroguanylin35 both stimulated cGMP release from cultured epithelial cells.35 The effects of linaclotide were abolished in ex vivo preparations where the mucosa was removed.34

These studies suggest that epithelial GC-C activation causes basolateral cGMP secretion, which decreases nociceptor activity, providing a biological mechanism for the clinical effects of GC-C agonists. We note that a recent study has challenged the dogma that enterocyte-derived cGMP is the main antinociceptive mediator of GC-C activation,36 as discussed in section 6.

Clinical trials

Linaclotide and plecanatide have been tested in multiple randomized controlled trials (RCTs) in IBS with constipation, summarized in a prior meta-analysis (for summary of all trials discussed see Table 1).37 Both were more efficacious than placebo in the effect on abdominal pain, according to the US Food and Drug Administration (FDA)-recommended end point for abdominal pain in IBS with constipation, consisting of a ≥30% improvement from baseline for ≥50% of weeks. However, delayed-release forms of linaclotide, developed based on the premise that ileocecal delivery of the drug targets abdominal pain without affecting bowel habit, were not superior to placebo over most abdominal pain measures in a phase II RCT.38

Treatment studiedConditionNo. of studiesNo. of patientsComparatorReported effect

Linaclotide, 290 μg q.d.	IBS-C	3 RCTs summarized in a meta-analysis37	2447	Placebo	RR of abdominal pain persistence = 0.79 (95% CI, 0.73–0.85)
Plecanatide, 6 mg or 3 mg q.d.	IBS-C	2 RCTs summarized in a meta-analysis37	2194	Placebo	RR of abdominal pain persistence = 0.84 (95% CI, 0.78–0.90) and 0.87 (95% CI, 0.81–0.93), respectively
Loperamide	IBS-D Unselected patients with IBS	2 RCTs54,55	24 60	Placebo Placebo	Abdominal pain score 3.0 vs −0.14, P < .05 2.2 days with abdominal pain vs 8.3 days, P < .01
Eluxadoline, 100 mg or 75 mg b.i.d.	IBS-D	4 RCTs summarized in a meta-analysis56	2758	Placebo	RR of abdominal pain persistence = 0.89 (95% CI, 0.83–0.96) and 0.95 (95% CI, 0.88–1.04), respectively
Psyllium (up to 10 g/d)	Unselected patients with IBS	2 RCTs89,90	80 178	Placebo Placebo	Abdominal pain mild or absent in 52.5% vs 57.5%, N/S RR of adequate relief of abdominal pain at 1, 2, and 3 months = 1.60 (95% CI, 1.13–2.26), 1.44 (95% CI, 1.02–2.06), and 1.36 (95% CI, 0.90–2.04), respectively
Bran (up to 10 g/d)	Unselected patients with IBS	1 RCT90	190	Placebo	RR of adequate relief of abdominal pain at 1, 2, and 3 months = 1.13 (95% CI, 0.81–1.58), 1.22 (95% CI, 0.86–1.72), and 1.70 (95% CI, 1.12–2.57), respectively
Low FODMAP diet	IBS IBD	12 RCTs summarized in a meta-analysis91 2 RCTs92,93	914 52 89	BDA dietary advice Habitual diet Sham diet Sham diet Habitual diet	RR of abdominal pain persistence = 0.78 (95% CI, 0.57–1.06) RR of abdominal pain persistence = 0.72 (95% CI, 0.47–1.10) RR of abdominal pain persistence = 0.51 (95% CI, 0.30–0.87) Abdominal pain severity score 22 vs 30, P = .098 and 36 days with abdominal pain vs 38 days, P = .78 OR for improvement in abdominal pain frequency = 2.97 (95% CI, 1.12–7.89)
Rifaximin, 550 mg t.i.d. for 2 weeks	Nonconstipated IBS	2 RCTs summarized in a meta-analysis56	1260	Placebo	RR of abdominal pain persistence = 0.95 (95% CI, 0.89–1.01
FMT	IBS with bloating Unselected patients with IBS UC	2 RCTs96,97 1 RCT98	62 165 20	Placebo Placebo Usual treatment	Abdominal pain score 2.80 vs 3.88 at baseline with FMT, P = .001, compared with 3.57 vs 3.79 at baseline with usual treatment, P = .205 Abdominal pain score 166.8 and 186.3 posttreatment with 60 mg and 30 mg FMT, respectively, vs 307.0 with placebo, P < .001 Abdominal pain score 0.9 vs 4.5 at baseline with FMT, P = .026, compared with 1.8 vs 4.9 at baseline with usual treatment, N/S
Gelsectan	IBS-D	1 RCT99	60	Placebo	Number of patients with totally to slightly unacceptable abdominal pain reduced from 67% at baseline to 0% at 4 weeks with gelsectan vs 83% to 60% with placebo, statistical significance not reported
Probiotics Combination probiotics Lactobacillus-containing strains Saccharomyces cerevisiae I-3856 Bifidobacterium-containing strains Bacillus-containing strains	All in unselected patients with IBS	32 RCTs100 11 RCTs100 5 RCTs100 3 RCTs100 3 RCTs100	3469 1183 1482 389 212	Placebo Placebo Placebo Placebo Placebo	RR of abdominal pain persistence = 0.72 (95% CI, 0.64–0.82) RR of abdominal pain persistence = 0.59 (95% CI, 0.45–0.76) RR of abdominal pain persistence = 0.64 (95% CI, 0.45–0.90) RR of abdominal pain persistence = 0.78 (95% CI, 0.64–0.95) RR of abdominal pain persistence = 0.33 (95% CI, 0.23–0.47)
Ketotifen (titrated from 2 mg to 6 mg b.i.d.)	Unselected patients with IBS	1 RCT109	60	Placebo	7% of patients reporting severe abdominal pain vs 28%, P = .02
Ebastine 20 mg o.d.	Unselected patients with IBS Nonconstipated IBS	1 RCT110 1 RCT111	55 202	Placebo Placebo	Relief of abdominal pain in 41% vs 20%, P = .19 ≥30% improvement in abdominal pain in 37% vs 25%, P = .081
Disodium cromoglycate, 600 mg/d	IBS-D	1 RCT112	43	No treatment	≥50% improvement in abdominal pain in 77% vs 28%, P = .002
Peppermint oil (usually 2 capsules t.i.d.)	Unselected patients with IBS	7 RCTs summarized in a meta-analysis119	748	Placebo	RR of abdominal pain persistence = 0.76 (95% CI, 0.62–0.93)
Red pepper (capsaicin)	Unselected patients with IBS FD	1 RCT120 1 RCT121	50 30	Placebo Placebo	Abdominal pain score 1.9 vs 2.7 at baseline with red pepper, compared with 2.3 vs 2.4 at baseline with placebo, reported as “statistically significant” Abdominal pain score 1.61 posttreatment vs 2.37, P < .05
Alosetron, 1 mg b.i.d.	IBS-D	6 RCTs summarized in a meta-analysis56	2606	Placebo	RR of abdominal pain persistence = 0.83 (95% 0.78–0.88)
Ramosetron, 5 μg or 2.5 μg o.d.	IBS-D	5 RCTs summarized in a meta-analysis56	1928	Placebo	RR of abdominal pain persistence = 0.82 (95% CI, 0.75–0.89) and 0.75 (95% CI, 0.65–0.85), respectively
Ondansetron, 12 mg q.d, bimodal release or titrated up or down from 4 mg o.d.	IBS-D	3 RCTs summarized in a meta-analysis127	327	Placebo	RR of abdominal pain persistence = 0.95 (95% CI, 0.74–1.20)
Tegaserod, 6 mg b.i.d.	IBS-C FD	Pooled analysis of 4 RCTs128 2 RCTs129	2886 1360 1307	Placebo Placebo Placebo	OR for abdominal pain response = 1.38 (95% CI, 1.14–1.67) Abdominal pain response rate 44.9% vs 40.0%, P = .027 Abdominal pain response rate 44.0% vs 42.3%, P = .51
SSRIs (eg, escitalopram, 10 mg o.d.)	Unselected patients with IBS FD	5 RCTs summarized in a meta-analysis132 1 RCT133	262 195	Placebo Placebo	RR of abdominal pain persistence = 0.82 (95% CI, 0.58–1.16) Upper abdominal pain score 1.4 posttreatment vs 1.2, N/S
TCAs (eg, amitriptyline, 10–30 mg o.d., or imipramine, 50 mg o.d.)	Unselected patients with IBS FD	4 RCTs summarized in a meta-analysis132 1 RCT134 2 RCTs133,135	171 463 194 107	Placebo Placebo Placebo Placebo	RR of abdominal pain persistence = 0.53 (95% CI, 0.34–0.83) OR for ≥30% improvement in abdominal pain = 1.66 (95% CI, 1.12–2.46) Upper abdominal pain score 1.1 post-treatment vs 1.2, N/S Epigastric pain score 0.96 vs 1.24 at baseline with imipramine, P = .026, compared with 0.96 vs 1.13 at baseline with placebo, P = .13
SNRIs (eg., venlafaxine 150 mg o.d.)	Unselected patients with IBS	1 RCT136	30	Placebo	Frequency of abdominal pain or discomfort score 3.87 vs 4.93, P = .03
Oloroinab, 10 mg to 100 mg t.i.d.	IBS with abdominal pain Crohn’s disease with abdominal pain	1 RCT147 1 randomized, open-label study148	273 14	Placebo N/A	56.5%, 59.7%, and 56.7% of 10 mg, 25 mg, and 50 mg t.i.d., respectively, achieved a ≥30% improvement in abdominal pain vs 52.9% with placebo, N/S
					Change in abdominal pain score from baseline of −4.61 with 25 mg t.i.d. and −4.57 with 100 mg t.i.d.
Pregabalin, 75 mg o.d., or titrated up from 75 mg b.i.d.	Unselected patients with IBS FD	1 RCT154 1 RCT155	85 72	Placebo Placebo	Abdominal pain score 28 posttreatment vs 40, P = .008 Epigastric pain score 3.0 posttreatment vs 4.0, P = .01

Table 1

Summary of Evidence for Efficacy of Available Treatments Directed Against Peripheral Mechanisms of Abdominal Pain in Their Effect on Abdominal Pain as an End Point

BDA, British Dietetic Association; b.i.d., twice daily; CI, confidence interval; IBS-C, IBS with constipation; N/A, not applicable; N/S, not significant; o.d., once daily; OR, odds ratio; q.d., once daily; RR, relative risk; t.i.d., 3 times daily.

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Peripherally Acting Opioids and Visceral PainPharmacology and preclinical studies

Opioids signal through 4 GPCRs: μ-opioid receptors (MORs), δ-opioid receptors (DORs), κ-opioid receptors (KORs), and nociceptin opioid receptors.39 The analgesic effect of conventional opioids can be strong (eg, oxycodone, morphine) or weak (eg, codeine) and predominantly result from activation of MORs, although DORs and KORs also play a role. On nociceptors, these receptors trigger GPCR-Gi/o protein signaling leading to the recruitment of multifunctional intracellular proteins, called β-arrestins, and sustained signaling by endosomes.40 This signaling modulates ion channels and, ultimately, inhibits action potential firing. Receptor expression‎ is increased in inflammatory conditions, including active IBD, possibly leading to altered signaling.41

Conventional opioids can exhibit potent analgesic actions, particularly for acute pain, but are limited by their adverse effect profile, including cognitive impairment, respiratory depression, nausea, constipation, and addictive potential.42 Analgesic tolerance leads to dose escalation and consequently greater risk of these potentially life-threatening adverse effects. Dose escalation is also implicated in the development of a paradoxical switch in signaling, leading to opioid-induced hyperalgesia, a poorly understood condition.43 The opioid crisis has hastened the search for safer alternatives, including peripherally restricted opioids that lack addictive potential and central adverse effects such as respiratory depression and cognitive impairment.

Strategies to develop peripherally acting opioids are being explored to identify safe, yet effective, analgesics for visceral pain. Access to the central nervous system can be restricted, for example, by creating charged molecules, and several compounds display peripheral analgesic actions,44,45 including loperamide, a MOR agonist.46 To date, however, these do not exhibit sufficient analgesic effects to be clinically useful to treat visceral pain.

Another strategy is to target opioid receptor heterodimers, such as eluxadoline,47 a MOR agonist and DOR antagonist with weak affinity for KORs. MORs and DORs are coexpressed on nociceptors innervating the intestine, and eluxadoline shows high binding affinity for MOR/DOR heterodimers in cell assays48 and functional interaction between receptors. However, there has been sparse mechanistic study in whole-animal models to clarify the role of this interaction further.49

There are other promising strategies to develop safe opiates, such as enhancing endogenous opioids (eg, enkephalinase inhibitors), by developing pH-sensitive opioid analogues,50 which are only active at sites of inflammation and thus lack the adverse effect profile and addictive potential of conventional opioids. Combinations of subthreshold opioids and cannabinoid receptor 1 (CB1) agonists can provide strong analgesia51 without adverse effects. Novel delivery systems using nanoparticles of between 1 and 100 nm in diameter, containing opioid cargoes,52 target intracellular signaling in endosomes and can be delivered intrarectally to act locally within the inflamed colon. To date, most of these strategies are based on preclinical studies and none have been tested adequately in humans. Finally, female rodents are less sensitive to opiate analgesia,53 and whether these strategies have sex-specific effects would be important to eval‎uate.

Clinical trials

Few trials have been conducted with new opioid-related drugs in visceral pain, largely due to the negative impact of the opioid crisis. Despite widespread use of loperamide in clinical practice, there is little evidence for this. One 13-week RCT, recruiting patients with IBS with diarrhea (IBS-D), reported pain scores were significantly lower with loperamide.54 In a second 3-week trial that recruited IBS of all subtypes, the number of painful days was reduced significantly with loperamide, but only in patients with alternating bowel habit.55 Both trials used historical definitions of IBS, did not conform to guidance for design of treatment trials in DGBI, and many participants did not report abdominal pain at all. More rigorous trials of loperamide are needed, although it is unlikely these will ever be conducted.

In contrast, eluxadoline has been tested rigorously in phase III RCTs at 2 doses, 75 mg or 100 mg twice daily, with data pooled in a prior meta-analysis.56 Only 100 mg twice daily was superior to placebo for the FDA-recommended end point for abdominal pain, but benefit was modest. In addition, there have been safety issues, with episodes of acute pancreatitis and sphincter of Oddi dysfunction reported.

The Microbiome and Visceral PainAdvances in pathophysiology

The involvement of gut microbiota in the development of visceral pain is largely based on preclinical studies measuring pain thresholds after transfer of human stool microbiota into germ-free rodents or administration of live biotherapeutics (probiotics) or antibiotics, or both, in rodent models. For instance, germ-free rats colonized with stool microbiota from individuals with IBS display decreased pain thresholds in response to rectal distention.57 Further insights have been gained from studies involving gnotobiotic mice, revealing the role of commensal microbes in maintaining normal excitability of gut intrinsic neurons.58

Perturbing the gut microbiome during early life using vancomycin leads to visceral hypersensitivity in rats.59 Conversely, administration of live biotherapeutics, such as Faecalibacterium prausnitzii, Lactobacillus paracasei NCC2461, or Lactobacillus GG, reduces visceral hypersensitivity and intestinal permeability in preclinical models that alter the early-life microbiome.60,61 Unlike in early life, antibiotic administration improves visceral hypersensitivity in adult mice,62 suggesting potential age-dependent effects of the microbiome.

Interestingly, visceral pain responses to colorectal distention vary across the estrous cycle in female mice, but this effect is lost in germ-free animals. Ovariectomy caused visceral hypersensitivity in specific pathogen-free, but not germ-free mice, suggesting an interaction between sex hormones, visceral pain, and the microbiome.63

Building on insights from animal models, human studies exploring fecal microbiome changes in patients with IBS have found specific taxa that positively (Proteobacteria)64 or negatively (Bifidobacterium spp) correlate with the severity of pain.65 Although human microbiome studies have focused largely on the colon, changes in small-intestinal microbial composition, rather than bacterial numbers, appear to differentiate patients with abdominal pain from healthy controls.66 However, the role of small-intestinal microbiota in the pathophysiology of abdominal pain remains unclear. Together, although findings from preclinical models and human studies underscore a role of the gut microbiome, whether these changes are causal to the development of visceral hypersensitivity or a consequence of changes in diet and gastrointestinal motility is unknown.

Gut microbiota-derived metabolites, neurotransmitters, toxins, and cell wall components have emerged as potential factors underlying the pathophysiology of visceral hypersensitivity. These bioactive compounds can (1) sensitize sensory neurons indirectly by stimulating either enteroendocrine cells, which release serotonin, or immune cells, which release chemokines and cytokines, both of which act on distinct neuronal populations, (2) disrupt the intestinal barrier, allowing passage of potentially noxious stimuli, and (3) activate sensory neurons directly, particularly in instances where barrier function is compromised (Figure 2). Most bacteria-derived compounds are pleiotropic, acting via multiple signaling pathways. Thus, they exert wide-ranging effects. Furthermore, gut microbiota can both synthesize and use neurotransmitters, encompassing excitatory, such as glutamate, histamine, dopamine, and norepinephrine, and inhibitory neurotransmitters, such as γ-aminobutyric acid (GABA).67 These neurotransmitters allow intercommunication among microbiota members and the host.

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Figure 2 Mechanisms underlying gut microbiome-driven visceral nociception. Gut microbiome-derived products can sensitize peripheral nociceptors directly or act indirectly by stimulating immune cells or enterochromaffin cells, or both, to release cytokines, chemokines, or serotonin, or a combination of these, respectively. The gut microbiome can also modulate intestinal barrier function by altering the luminal bile acid and protease pool or through metabolites such as butyrate. AHR, aryl hydrocarbon receptor; CA, carboxylic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; FFAR, free fatty acid receptor; FXR, farnesoid X receptor; GPR35, G protein-coupled receptor 35; LCA, lithocholic acid; LPS, lipopolysaccharide; LTS, leukotrienes PAMPs, pathogen-associated molecular patterns; PAR2, protease activated receptor 2; PGN, peptidoglycan; TGR5, Takeda G protein-coupled receptor 5; TLR, Toll-like receptor.

Enterochromaffin cells are the primary cell type responsible for peripheral serotonin production. They are polymodal chemosensors, capable of detecting specific luminal signals via an array of receptor pathways and translating them to the enteric nervous system by modulating serotonin-sensitive primary afferent nerves.68 Catecholamine neurotransmitters, such as norepinephrine and dopamine, initiate the adrenoceptor alpha 2A (Adrα2A) and the transient receptor potential cation channel subfamily C member 4 (TRPC4) signaling cascade.

On the other hand, short-chain fatty acids (SCFAs) and branched-chain fatty acids, such as isovaleric acid and, to a lesser extent, butyrate, activate the olfactory receptor 558 and P/Q type Cav channel within enterochromaffin cells.68 A multitude of bacterial metabolites, including butyrate, also augment serotonin synthesis within enterochromaffin cells.69 The role played by serotonin in modulating visceral pain, as well as the critical role of enterochromaffin cells in isovalerate-induced visceral hypersensitivity, is discussed further below.

Pathogen-associated molecular pattern molecules, which include bacterial cell wall components such as lipopolysaccharide, bind to pattern recognition receptors such as Toll-like receptors, are present on immune cells and sensory neurons. Pathogen-associated molecular pattern molecules contribute to visceral hypersensitivity by influencing nociceptors directly or by affecting immune cells indirectly, leading to peripheral sensitization.70,71 Diet-derived metabolites from bacterial fermentation, such as SCFAs, indole and indole derivatives, and kynurenine, also modulate visceral nociception. Butyrate exerts antinociceptive effects72 via peroxisome proliferator-activated receptors suppressing the activity of nuclear factor κ-light-chain-enhancer of activated B cells, involved in pain and inflammation.73,74

Butyrate also augments intestinal barrier function via activation of hypoxia inducible factor,75 regulates immune cells via free fatty acid 2/3 receptors,76 and drives epigenetic changes. Tryptophan is converted by microbes to kynurenic acid77 or to indole derivatives,78 both of which exert anti-inflammatory effects via G protein-coupled receptor 35 and aryl hydrocarbon receptor, respectively,79,80

Gut bacteria play an important role in determining the luminal bile acid and protease pool. Bile acid metabolites, including deoxycholic acid, regulate pain through the activation of G protein-coupled bile acid receptor 1, and are present in both primary sensory neurons and macrophages. Proteases contribute to visceral hypersensitivity by targeting intestinal barrier function81 as well as by signaling directly through protease activated receptor 2, present on neurons.82 The luminal protease pool depends on the balance between bacterial proteases83 and suppression of host proteases by bacteria harboring β-glucuronidases.81

The identification of distinct microbiota-driven mechanisms opens the door for novel therapeutic strategies. Currently, microbiota-targeted interventions largely focus on augmenting intestinal barrier function. In preclinical studies, fiber maintained both microbial diversity and barrier function,84 and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) was found to preserve barrier function by decreasing lipopolysaccharide-mediated mast cell activation.85

Clinical trials

There are a multitude of methods to manipulate the microbiome, and thereby microbial metabolites, as a means of treating abdominal pain. SCFA enemas have been studied in IBD, but trials have not reported an effect on abdominal pain.86–88 Fiber has been assessed in IBS, but few trials report abdominal pain outcomes.89,90 One 12-week RCT found there was no benefit of psyllium, a soluble fiber, over placebo,89 but in another trial of psyllium, bran, or placebo, significant improvements in abdominal pain occurred with both psyllium and bran at several time points.90

A network meta-analysis of 12 trials studied the effect of a low FODMAP diet on abdominal pain.91 It was superior to a sham diet but was not superior to standard British Dietetic Association dietary advice for IBS or habitual diet. In contrast, in a RCT comparing a 4-week low FODMAP diet with a sham diet in patients with quiescent IBD with persistent gastrointestinal symptoms, abdominal pain severity and days with abdominal pain did not differ.92 In another 6-week trial of a low FODMAP diet vs normal diet in patients with IBD in remission with ongoing gastrointestinal symptoms, response for abdominal pain frequency, but not severity, was significantly higher with the low FODMAP diet.93 Abdominal pain response rates with rifaximin, a minimally absorbed antibiotic, according to the FDA-recommended end point, were reported in a meta-analysis.56 There was no benefit with rifaximin over placebo.

Although there have been multiple RCTs of fecal microbial transplant (FMT) in both IBS and IBD, summarized in prior meta-analyses,94,95 few report impact of FMT on abdominal pain. Two RCTs of FMT in IBS studied this end point.96,97 One 12-week trial of a single FMT via nasojejunal tube in IBS with predominant bloating reported abdominal pain scores were significantly reduced.96 In the second RCT, 30 mg or 60 mg of a single FMT via gastroscopy led to a significant reduction in abdominal pain at 3 months vs placebo.97 One RCT comparing FMT with usual therapy in active ulcerative colitis reported abdominal pain scores improved significantly with FMT at 2 weeks compared with baseline, but also improved significantly in the usual therapy arm.98

Gelsectan, a prebiotic with mucoprotective and bifidogenic effects, which may reinforce the intestinal barrier, was studied in 1 crossover trial.99 The number of participants with totally to slightly unacceptable abdominal pain was reduced from baseline to 4 weeks compared with placebo. Finally, in a meta-analysis certain combinations of probiotics, Lactobacillus-containing strains, Saccharomyces cerevisiae I-3856, and Bifidobacteria- and Bacillus-containing strains improved abdominal pain, but certainty in the evidence was low to very low across the studies, with heterogeneity between individual trials in most analyses.100

Histamine and Visceral PainPharmacology and preclinical studies

Histamine functions as a paracrine signaling molecule that can activate nociceptors in the gastrointestinal tract (Figure 3). It is a member of the biogenic amine family and is synthesized from l-histidine exclusively by l-histidine decarboxylase.101 Histamine signaling to nociceptors in the gut could originate from 2 sources: intestinal tissue or the lumen. In tissue, it is stored in high concentrations, predominantly in mast cells, but also in basophils and eosinophils. However, other cells in the gut also express histidine decarboxylase, including macrophages, neutrophils, platelets, and dendritic cells, and can synthesize and release histamine but do not store it.102 In the lumen of the gastrointestinal tract, there are 3 possible sources: synthesis by microbiota, ingestion of histamine-rich foods, and histamine released from tissues that permeates into the lumen.

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Figure 3 Novel mechanisms causing increased histamine signaling to intestinal nociceptors. (A) This schema shows that after combined food antigen (red triangle) and acute self-limiting colitis or combined food antigen and psychological stress exposure, reexposure to food antigen alone triggers increased IgE release within the intestine (which is not systemic), causing mast cell degranulation within the intestinal wall. The ensuing histamine release causes nociceptor sensitization and increased pain signaling. (B) This schema shows that ingestion of poorly absorbed complex carbohydrates (CHO) (eg, FODMAPs) can stimulate microbial production of histamine. Patients with Klebsiella aerogenes produce up to 100 times more histamine than those lacking this bacterium in their stool samples. Luminal histamine stimulates H4 and H1 receptors, leading to mast cell degranulation with ensuing nociceptor sensitization and increased pain signaling. DRG, dorsal root ganglia.

Histamine is metabolized by 2 dominant pathways, histamine-N-methyltransferase and diamine oxidase,103 resulting in N-methyl histamine and imidazole acetaldehyde metabolites, respectively. These metabolites also exhibit biological activity (eg, N-methyl histamine), and the preponderance of the pathways may differ between mast cells and microbiota.

Histamine, and possibly some metabolites, can activate 4 GPCRs, H1 to H4.101 These GPCRs signal intracellularly via Gq and cyclic adenosine monophosphate to modulate passive and voltage-gated ion channels on nociceptors and other effector pathways in nonneuronal cells. The distribution of these receptors within the gut suggests histamine activates pain signaling directly through activation of neurons and indirectly via immune cell activation (Figure 3).

In humans,104 H1 receptors are found on connective tissues cells, immune cells, enterocytes, smooth muscle cells, and nerves, H2 receptors are found on gastric parietal cells, enterocytes, immunocytes, enteric nerves, and smooth muscle cells, and H4 receptors are expressed on immune cells, blood vessels, nerves, and enterocytes. H3 receptors have yet to be identified in humans.

Previous studies highlight the role of histamine in patients with IBS, demonstrating increased levels of histamine (and proteases) in mucosal biopsy specimens from patients compared with healthy controls, evidence of mast cell activation, and the ability of histamine in tissue supernatants from patients to exaggerate activation of rodent and human nociceptive neurons.105 Sex differences have not been described. More recent studies show increases in duodenal eosinophils in patients with FD, another source of tissue histamine, implicating a role in abdominal pain in this disorder.106 The triggers resulting in abnormal mast cell-histamine signaling observed in these patients have been unclear, but recent preclinical studies suggest multiple possible etiologies, as outlined below.

When mice develop a self-limiting bacterial colitis and are exposed simultaneously to a food antigen, and then reexposed to the food antigen alone after resolution of infection, they lose oral tolerance to the food antigen.14 This leads to visceral hypersensitivity and mast cell activation with histamine release. This exaggerated pain signaling was blocked by an H1 receptor antagonist, which inhibits histamine signaling to neurons, and by an IgE antibody, which prevents mast cell activation. Tissues exhibited elevated IgE levels, consistent with loss of oral tolerance, but there was no systemic increase in IgE, highlighting immune activation was confined to the intestine.

Injection of common antigens into the rectal mucosa in patients with IBS caused greater wheal and flare responses, compared with healthy volunteers, consistent with the hypothesis that some patients with IBS are sensitized to food antigens.14 Recent preliminary studies suggest psychological stress can also induce loss of oral tolerance to food antigens and lead to mast cell-histamine–mediated visceral hypersensitivity in both the small intestine and colon, a feature observed in many patients with IBS.107

Histamine production by the microbiota may be stimulated by poorly absorbed complex carbohydrates. In a study using germ-free mice to create a humanized IBS mouse model with fecal microbiota from patients with IBS and healthy controls,108 mice given fecal samples from patients with IBS who were high histamine producers, based on stool and urine samples, exhibited visceral hyperalgesia. This exaggerated pain signaling was blocked by H1- and H4- receptor antagonists, suggesting several signaling pathways were involved (Figure 3). Some of the histamine in the luminal samples could originate from the host (eg, mast cell degranulation). However, high histamine producers were found to have microbial species, including Klebsiella aerogenes, in their stool that could make up to 100 times more histamine than those without.

Clinical trials

Drugs targeting histamine receptors or stabilizing mast cells have not been well studied in gastrointestinal diseases. An 8-week trial of ketotifen, a H1-receptor antagonist, in IBS reported a significant improvement in abdominal pain over placebo.109 Ebastine, another H1-receptor antagonist, has been assessed in IBS.110,111 A 12-week proof-of-concept RCT found rates of relief of abdominal pain were numerically higher with ebastine, but not significantly so. In a subsequent phase IIb placebo-controlled trial, rates of abdominal pain improvement were higher with ebastine, although this was not significant.111 The effect of the mast cell stabilizer disodium cromoglycate on abdominal pain was studied in a RCT in IBS-D.112 In this 6-month study, compared with no treatment, significantly more patients randomized to disodium cromoglycate experienced abdominal pain improvement.

Transient Receptor Potential Vanilloid 1 and Visceral PainPharmacology and preclinical studies

TRPV1 is a nxxxxonselective ligand-gated cation channel that is highly enriched in gastrointestinal tract nociceptors. It is activated by polymodal stimuli, including mechanical stretch, noxious heat, low pH, exogenous chemical irritants, such as capsaicin (the active ingredient in chili peppers), and endogenous lipid metabolites of arachidonic acid (eg, the endocannabinoid anandamide113). Selective ablation of colon-projecting TRPV1-expressing neurons decreased nociception in response to colorectal distention in mice,22 highlighting its critical role in visceral pain. Estrogens can modulate lumbosacral dorsal root ganglia TRPV1 expression‎, suggesting a potential mechanism for sex differences in visceral pain.114

Sensitization of TRPV1 by inflammatory mediators, such as histamine,110 is one of the key pathways in mediating peripheral visceral hypersensitivity, as discussed above. However, TRPV1 expression‎ does not necessarily correlate with receptor sensitization. For example, in patients with IBS who were hypersensitive to rectal distention, rectal application of capsaicin caused increased pain perception. No change in TRPV1 expression‎ was noted when comparing hypersensitive and normosensitive patients with IBS, suggesting that although TRPV1 expression‎ is important, additional factors, such as receptor sensitization or central factors, or both, are necessary in mediating visceral pain.115

Although most of the studies have focused on TRPV1 sensitization in IBS and FD,113 TRPV1 may also play a role in chronic visceral pain in patients with IBD in remission. Rectal TRPV1 expression‎ was increased in patients with IBD in endoscopic remission with chronic visceral pain and correlated with patient-reported symptoms.116 Visceral hyperalgesia was TRPV1-dependent in postinflammatory mice,117 and they also displayed increased SCFA-producing microbiota and stool SCFA content. These microbial-derived SCFAs increased capsaicin-evoked calcium responses in the postinflammatory state, suggesting that microbial metabolites can sensitize TRPV1.118

Clinical trials

Peppermint oil, as well as being a smooth muscle relaxant, may have effects on TRPV1 signaling. A meta-analysis showed it was more efficacious than placebo for abdominal pain.119 However, benefit was modest, with heterogeneity between studies, and most trials did not use FDA-recommended end points. Although capsaicin stimulates the TRPV1 receptor, leading to worsening abdominal pain, repeated administration down-regulates the receptor. A 6-week trial in IBS showed abdominal pain scores were significantly lower, compared with baseline, in patients receiving red pepper pills compared with those receiving placebo.120 A similar 5-week study in FD demonstrated a significant reduction in epigastric pain scores with red pepper vs placebo.121 However, patients in both trials randomized to red pepper dropped out due to pain exacerbations.

Serotonin (5-Hydroxytryptamine) and Visceral PainPharmacology and preclinical studies

The monoamine neurotransmitter 5-hydroxytryptamine (5HT) plays an integral role in initiation of intrinsic gut reflexes regulating motility, secretion, and vasodilation. It also participates in the pathogenesis of visceral pain via afferent nerve 5-HT3 and 5-HT4 receptors; drugs that modulate these receptors have been used extensively in the treatment of visceral hypersensitivity.122 The actions of 5HT are terminated by the serotonin selective reuptake transporter, a peripheral target of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and serotonin norepinephrine reuptake inhibitors122 (SNRIs).

Genetic polymorphisms in the 5-HT3 receptor and the serotonergic synthetic enzyme, tryptophan hydroxylase, are associated with increased IBS susceptibility, whereas SSRI transporter polymorphisms are associated with both IBS and FD.123 Multiple studies report changes in 5HT synthesis, reuptake, and release in IBS,124 suggesting dysregulated 5HT signaling contributes to the pathophysiology of visceral pain. Surprisingly, few studies eval‎uating the role of TCAs in visceral pain have been performed in rodent models.

Although 5HT can be secreted by enteric neurons and mucosal mast cells, most of the body’s 5HT is synthesized and stored by enterochromaffin cells.122 Enterochromaffin cells are electrically excitable, and display axon-like basal processes, forming functional connections with extrinsic and intrinsic afferent neurons, termed neuropods.68,125 Enterochromaffin cells function as luminal sensory transducers, releasing 5HT in response to dietary nutrients and microbial products, as well as mucosal distortion via mechanosensitive Piezo-02 channels.126 5HT release by enterochromaffin cells, thus initiates intrinsic gut reflexes and stimulates extrinsic nerves.

A recent study eval‎uated the role of a mucosal afferent-enterochromaffin cell circuit in the pathogenesis of visceral hypersensitivity using transgenic mice,26 where enterochromaffin cells could be activated or silenced selectively. Direct activation of enterochromaffin cells elicited 5HT release and was sufficient to cause both acute and chronic visceral hypersensitivity to colorectal distention. Remarkably, activation of enterochromaffin cells was sufficient to elicit anxiety-like behavior in mice. These effects were inhibited by the 5HT3 antagonist alosetron, which decreased mucosal afferent activity. Conversely, silencing activity of enterochromaffin cells attenuated 5HT release and visceral hypersensitivity mediated by the microbial metabolite, isovalerate, in male mice. The mucosal afferent-enterochromaffin cell circuit demonstrated high tonic activity in female, but not male, mice suggesting a sex-specific contribution to pain signaling. Together, these data demonstrate that the enterochromaffin cell-mucosal afferent circuit plays an essential role in pathogenesis of visceral hypersensitivity.26

It is possible that the GC-C pathway also regulates 5HT secretion from enterochromaffin cells. GC-C is expressed not only by enterocytes but also by a subtype of monoamine synthesis-expressing neuropods enriched in the proximal intestine of mice.36 GC-C enriched neuropods formed functional connections with nociceptors in cocultures and caused spontaneous nociceptor activation, which was abolished by linaclotide. The antinociceptive effects of linaclotide on the response to colorectal distention were lost in mice that were deficient in neuropod GC-C.36 Thus, it is possible that enterochromaffin GC-C activation regulates 5HT tone, but whether this mechanism is active in vivo is unclear.

Clinical trials

The efficacy of the 5HT3-receptor antagonists alosetron and ramosetron, according to the FDA-recommended end point for abdominal pain, has been reported in multiple trials in IBS-D, pooled in a meta-analysis.56 Ramosetron, 2.5 μg daily and 5 μm daily, and alosetron, 1 mg twice daily, were superior to placebo, although alosetron has been associated with ischemic colitis. Varying doses of ondansetron, another 5HT3-receptor antagonist with a long history of safety, were assessed in 3 trials in IBS-D, summarized in another meta-analysis.127 The drug was not superior to placebo for pain.

For 5HT4-receptor agonists, in a pooled analysis of data from 4 RCTs in IBS, tegaserod, 6 mg twice daily, was more efficacious for pain than placebo.128 In two 6-week trials of tegaserod in FD, 6 mg twice daily was superior to placebo for abdominal pain in 1 RCT but not the other.129 Safety issues arising from cardiovascular and cerebrovascular ischemic events led to the withdrawal of tegaserod. Although it was reintroduced briefly, tegaserod is now no longer available. Prucalopride was assessed in chronic constipation and was efficacious,130 but no RCTs report its efficacy in improving abdominal pain, and it has never been tested in IBS or FD.

Although SSRIs, TCAs, and SNRIs are antidepressants, in the context of treating abdominal pain, they act as gut-brain neuromodulators involving, at least in part, 5-HT131; discussion of the central actions of these compounds is beyond the scope of this review. SSRIs have been assessed in IBS and FD, with no impact on abdominal pain in IBS in a prior meta-analysis,132 and a reduction in pain scores in FD in a single RCT of escitalopram, 10 mg once daily, but with no benefit over placebo.133 TCAs, however, were more efficacious than placebo for abdominal pain in IBS in a meta-analysis of 4 RCTs132 and more recently in a 6-month trial in 463 patients.134 In one 12-week trial in refractory FD, imipramine led to a significant reduction in epigastric pain scores vs placebo,135 but another trial of amitriptyline demonstrated no benefit.133 The SNRI venlafaxine was assessed in a single 12-week RCT in IBS; abdominal pain frequency scores were reduced significantly compared with placebo.136 An RCT of FD did not report its effect on abdominal pain.137

Cannabinoids and Visceral PainPharmacology and preclinical studies

Cannabinoids are widely used alternative therapies to treat abdominal pain in both IBD and IBS.138,139 The actions of cannabinoids are mediated via the endocannabinoid system, which regulates gastrointestinal motility, secretion, immune function, intestinal permeability, and visceral hypersensitivity.140

The classical components of the endocannabinoid system are the endogenous cannabinoid ligands, anandamide, and 2-arachidonoylglycerol, as well as their biosynthetic and degradative enzymes. These are found throughout the microbiota-gut-brain axis, including the epithelium, enterochromaffin cells, enteric nervous system, and immune system, as well as extrinsic afferent nerves, where they primarily exert an antinociceptive effect. Anandamide is also an agonist at TRPV1. Thus, endocannabinoids have both pronociceptive and antinociceptive effects, depending on the receptor.140 Interestingly, commensal bacteria can produce endocannabinoid-like molecules,141 although whether a microbial source of endocannabinoid-like molecules plays a role in visceral hypersensitivity is unknown.

In animal models of stress-induced visceral hypersensitivity and in postinflammatory models, CB1 and CB2 agonists decrease the visceromotor response to colorectal distention.140,142–144 Endocannabinoids can either exert their antinociceptive actions directly via CB1 and CB2 receptors expressed on nociceptors142,145 or indirectly via down-regulation of mast cell or macrophage activation.140 However, clinical use of cannabinoids is hampered by psychotropic adverse effects. Accordingly, there has been interest in synthesizing peripherally restricted cannabinoid receptor agonists.142–144

A recent preclinical study of the peripherally restricted CB2 receptor agonist, olorinab, was performed in rodent models of acute colitis and postinflammatory visceral pain.142 Olorinab reversed the colitis-induced hypersensitivity to colorectal distention in both the acute and postinflammatory state; no effects on visceral pain were seen when olorinab was given to controls. Olorinab was able to decrease mechanosensitivity of ex vivo afferent nerves in a dose-dependent manner, both in acute colitis and in the postinflammatory state, although CB2 expression‎ was not up-regulated in afferent nerves compared with controls.142 Unfortunately, only male mice were eval‎uated in this study, although CB2 expression‎ is increased in female patients with IBS.146 These data suggest CB2 receptors on visceral afferents are sensitized by inflammation and, in turn, play a regulatory anti-nociceptive role.

Clinical trials

In a 12-week phase II dose-ranging study of olorinab in IBS, the proportion of patients experiencing improvement in abdominal pain was not significantly higher with any dose studied.147 However, in those with moderate to severe pain at baseline, abdominal pain scores were significantly improved with 50 mg 3 times daily. No placebo-controlled trials of this drug in IBD have been conducted, although an 8-week open-label randomized study recruiting patients with Crohn’s disease who reported abdominal pain found a significant reduction in pain scores from baseline with olorinab.148 There is no evidence for other drugs acting on cannabinoid receptors for treating abdominal pain in gastrointestinal disorders.149

γ-Aminobutyric Acid and Visceral PainPharmacology and preclinical studies

Functional GABA receptors have been identified in the nerve terminals of colonic afferents. The activation of GABA receptors (GABAA and GABAB) by endogenous GABA decreases sensitivity of colonic afferents, whereas GABAA activation also reduces visceral pain perception.150 Functional GABAergic transmission has also been found in nociceptors, producing strong analgesic effects.151 In addition to endogenous production, certain bacteria expressing glutamate decarboxylase, can produce GABA from glutamate.67 In rodent models, GABA-producing bacteria have an analgesic effect in stress-induced152 and fecal-retention153 models of visceral hypersensitivity.

Clinical trials

There has been 1 RCT of pregabalin in both FD and IBS, but no trials in other painful gastrointestinal disorders and no trials of gabapentin. Abdominal pain scores were significantly lower in patients assigned to titrated pregabalin vs placebo in a 12-week trial in IBS.154 Similarly, pregabalin, 75 mg daily, was superior to placebo for epigastric pain scores in an 8-week trial in FD.155

Conclusions

Chronic visceral pain represents a substantial burden to patients. Despite the potential for the evidence-based treatments described above, a need remains for the development of novel therapeutics to treat sensitization of peripheral pain pathways effectively. Future directions should include the identification of microbial vs host sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), similar to current work eval‎uating histamine (Figure 4).

Figure viewer

Figure 4 Areas for future investigation in peripheral mechanisms of visceral pain. There is a need to identify peripheral mechanisms underlying visceral pain and develop novel therapeutic agents to treat patients. Identification of microbial vs host sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), is one such mechanistic area. Eval‎uation of the relative contribution of each pathophysiologic mechanism to nociceptor sensitization in individual patients, and thus use of combination therapies targeting these mechanisms, is key. For opiates, some promising strategies for the development of safe yet effective opiate therapies are the development of pH-sensitive opiate analogues active at the site of inflammation, use of peripherally restricted agents or subthreshold combinations of opiates, and CB1 receptor agonists. Because chronic visceral pain is more common in women, future studies should eval‎uate whether pain mechanisms are sex-specific and whether treatments should be used in a sex-specific manner. ♀, female; ♂, male.

With respect to the microbiome, research should avoid observational-based community profiling and focus on mechanistic approaches eval‎uating how microbiota or microbial products, or both, interact with nociceptors. Methods to test the relative contribution of each pathophysiologic mechanism to the sensitization of peripheral nociceptors and their role in overlapping pain syndromes in individual patients is also required. This would allow the use of specific drug combinations to target multiple mechanisms synergistically.

Given the sex bias of chronic visceral pain, future studies should eval‎uate whether pain mechanisms are sex-specific or whether treatments should be used in a sex-specific manner. Identifying whether differing or similar peripheral mechanisms are involved in the development of chronic visceral pain in patients with IBD vs painful DGBI will be important. Finally, eval‎uation of the relative contribution of peripheral vs central sensitization to symptoms would be important to individualize patient therapy. Continued multidisciplinary collaboration between clinician-scientists and bench-based scientists with the use of innovative reverse translational approaches is necessary to advance this field, identify new target pathways, and improve the clinical management of patients.

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Reviews in Basic and Clinical Gastroenterology and HepatologyVolume 166, Issue 6p976-994June 2024Open access

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Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments

Alexander C. Ford1,2,∗ ∙ Stephen Vanner3,∗ ∙ Purna C. Kashyap4 ∙ Yasmin Nasser5 ynasser@ucalgary.ca

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Abstract

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

Keywords

1. Visceral Pain
2. Inflammatory Bowel Disease
3. Irritable Bowel Syndrome
4. Histamine
5. Serotonin
6. Microbiome
7. Abdominal Pain
8. Inflammation

Abbreviations used in this paper

1. HT (5-hydroxytryptamine)
2. CB1 (cannabinoid receptor 1)
3. cGMP (guanosine 3′,5′-cyclic monophosphate)
4. DGBI (disorders of gut-brain interaction)
5. DOR (δ-opioid receptor)
6. FD (functional dyspepsia)
7. FDA (Food and Drug Administration)
8. FMT (fecal microbial transplant)
9. FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols)
10. GABA (γ-aminobutyric acid)
11. GC-C (guanylate cyclase-C)
12. GPCRs (G protein-coupled receptors)
13. IBD (inflammatory bowel disease)
14. IBS (irritable bowel syndrome)
15. IBS-D (inflammatory bowel disease with diarrhea)
16. KOR (κ-opioid receptor)
17. MOR (μ-opioid receptor)
18. RCT (randomized controlled trial)
19. SCFA (short-chain fatty acid)
20. SNRI (serotonin norepinephrine reuptake inhibitor)
21. SSRI (selective serotonin reuptake inhibitor)
22. TCA (tricyclic antidepressant)
23. TRP (transient receptor potential)
24. TRPV1 (transient receptor potential vanilloid 1)
25. US (United States)

Pain, defined as an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage, can be acute or chronic.1 It can originate from somatic (muscle, bone, or soft tissue) or visceral (thoracic, abdominal, or pelvic organs) structures.1 Visceral pain is one of the most challenging clinical conditions facing patients and their health care providers. It is extremely common. Abdominal pain is a key reason that patients with gastrointestinal disorders, such as inflammatory bowel disease (IBD) or disorders of gut-brain interaction (DGBI), including irritable bowel syndrome (IBS) or functional dyspepsia (FD), seek medical attention.2,3 More than 70% of patients with IBD experience abdominal pain during an acute flare,4 and between 20% and 60% report chronic abdominal pain.5 Chronic visceral pain is a hallmark of some DGBI, which affect up to 40% of adults, primarily women, worldwide.6

The diagnosis and treatment of chronic visceral pain is difficult, largely because it is poorly localized and difficult to describe due to the relatively small density of nerve terminals in the viscera and the divergent projections into the spinal cord,7 and because the pathophysiology remains incompletely understood. Chronic visceral pain is, thus, a significant burden to patients and is associated with anxiety, depression, decreased quality of life, and increased direct and indirect health care costs.5,8,9 IBS alone is estimated to cost the United States (US) ∼US $350 million each year for outpatient clinic visits, not including diagnostic testing, medications, nonpharmacologic therapies, or indirect costs due to lost productivity.10 Unfortunately, these challenges have been further amplified by the opioid crises.11,12 This highlights the continued need for advances in understanding of the pathophysiology of visceral pain to enable both effective and safe therapies.

Chronic visceral pain is a disorder of the microbiota-gut-brain axis, and central and peripheral mechanisms both contribute to its pathogenesis (Figure 1). Triggers include stress, psychological comorbidities, such as anxiety or depression, diet, low-grade intestinal inflammation, and microbial dysbiosis.4,13–15 Most abdominal pain signaling originates from nociceptors (pain-sensitive neurons), called visceral primary afferent nerves, whose cell bodies lie in the dorsal root ganglia and which have pseudo-unipolar axons connecting the intestine and the spinal cord.16 Nociceptors synapse with second-order neurons in the thoracolumbar and lumbosacral spinal cord17 and thereafter with central ascending pain pathways. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways originating from the hypothalamus and midbrain.18

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Figure 1 Chronic visceral pain is a disorder of the gut-brain axis. Nociceptors have cell bodies that lie in the dorsal root ganglia (DRG) and pseudounipolar axons that connect the intestine and the spinal cord. These synapse with second-order neurons in the spinal cord and with central ascending pathways thereafter. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways. (Inset) At the level of the mucosa, nociceptive terminals are both mechanosensitive and chemosensitive and are stimulated by luminal factors (eg, microbial products and nutrients) as well as by host mediators released due to infection, inflammation, or tissue damage (eg, serotonin, histamine, proteases, chemokines, and cytokines). These mediators can act indirectly via the epithelium/enterochromaffin cells or can stimulate nociceptors directly if there is a breakdown in the mucosal barrier. This results in sensitization of ion channels such as TRP, resulting in increased visceral pain.

Sensitization of nociceptors, defined as a decrease in the threshold for stimulation and an increase in the magnitude of the response,19 can occur peripherally, in the central nervous system, or both. This results in hyperalgesia, a heightened response to painful stimuli, and allodynia, which is pain arising from nonpainful stimuli.19 Central sensitization may also result in comorbid pain involving different organ systems,20 a discussion of which is beyond the scope of this review.

At the level of the periphery, nociceptive nerve terminals are found in muscle and serosa as well as in the mucosa.7 Nociceptors are mechanosensitive and are stimulated by stretch or distention.16 These actions are mediated by a variety of mechanosensitive ion channels, such as the transient receptor potential (TRP) receptors, including TRP vanilloid 1 (TRPV1) and 4, and TRP ankyrin 1, the 2-pore domain potassium channel family, the degenerin/epithelial sodium channel family, including the acid-sensing ion channels 1, 2, and 3, and the piezo-type mechanosensitive ion channel component 2 (Piezo-02).21,22

Nociceptors at the mucosal level are also chemosensitive and are stimulated by luminal factors, such as microbial products and nutrients, as well as by chemical mediators released during tissue infection, inflammation, or damage. These include bacterial toxins, neurotransmitters, proteases, bioactive amines, such as histamine, and serotonin, neurotrophins, adenosine-5′-triphosphate, chemokines, and cytokines (Figure 1, inset).13,23 Luminal products can either stimulate nociceptors directly, particularly if there is associated breakdown in the mucosal barrier as seen in both IBD and IBS,24,25 or indirectly via the epithelium or enteroendocrine cells.26

Chemical compounds and luminal products can, in turn, stimulate pronociceptive G protein-coupled receptors (GPCRs) or lead to increased expression‎ and activation of ion channels, such as TRP or voltage-gated sodium and calcium channels, or can decrease potassium channel activation and expression‎, resulting in peripheral sensitization. In turn, nociceptors can release neurotransmitters, such as substance P and calcitonin gene-related peptide, which augment the inflammatory response in the periphery and activate second-order neurons in the spinal cord, leading to neurogenic inflammation13,23 (Figure 1, inset).

Building on this pathophysiological framework, this review will focus on recent advances in visceral peripheral pain neurotransmission and mechanisms that result in sensitization of afferents in patients with IBD or painful DGBI. It will discuss specific physiologic and pathophysiologic preclinical peripheral mechanisms that have been translated into receptor-based treatment approaches for visceral pain in clinical trials. Some of these treatments have targeted advances in the physiology of nociceptors or intermediary cells, or both, whereas others target new understanding of pathophysiologic mechanisms of specific disorders.

Mechanistic Advances and the Resulting TherapiesGuanylate Cyclase-C and Visceral PainGuanylate cyclase-C pharmacology and preclinical studies

The enterocyte receptor guanylate cyclase-C (GC-C) plays an essential role in fluid secretion, barrier function, and nociception. Drugs such as linaclotide and plecanatide have taken advantage of this homeostatic system to treat visceral pain. GC-C is found on the apical surface of enterocytes throughout the gastrointestinal tract and is activated by the paracrine hormones uroguanylin and guanylin.27 Activation of GC-C triggers enzymatic conversion of guanosine-5ʹ-triphosphate to guanosine 3′,5′-cyclic monophosphate (cGMP), which in turn regulates activity of the apical cystic fibrosis transmembrane conductance regulator, leading to increased luminal chloride and bicarbonate secretion and a secondary increase in intestinal motility.27 Genetic mutations in the guanylate cyclase 2C gene (GUCY2C) have been found in patients with congenital secretory diarrhea28 and may predispose patients to IBD,29 whereas dysregulated GC-C expression‎ has been implicated in the pathophysiology of both IBD30 and IBS.31 Sex differences have not been reported.32

Epithelial GC-C signaling has a key role in nociception. Linaclotide, a minimally absorbed GC-C agonist, decreased the visceral motor response to colorectal distention in both acute colitis and stress-induced models of visceral hypersensitivity. The effects of linaclotide were abolished in GC-C–knockout animals, confirm‎ing its specificity.33 Linaclotide34 or direct application of cGMP34,35 to an ex vivo preparation of nociceptor afferents decreased response to circumferential stretch in control animals as well as in acute colitis35 and in postinflammatory34 models of visceral pain. GC-C expression‎ was not found on nociceptors,34,35 suggesting its antinociceptive effects were indirect. Indeed, linaclotide34 and uroguanylin35 both stimulated cGMP release from cultured epithelial cells.35 The effects of linaclotide were abolished in ex vivo preparations where the mucosa was removed.34

These studies suggest that epithelial GC-C activation causes basolateral cGMP secretion, which decreases nociceptor activity, providing a biological mechanism for the clinical effects of GC-C agonists. We note that a recent study has challenged the dogma that enterocyte-derived cGMP is the main antinociceptive mediator of GC-C activation,36 as discussed in section 6.

Clinical trials

Linaclotide and plecanatide have been tested in multiple randomized controlled trials (RCTs) in IBS with constipation, summarized in a prior meta-analysis (for summary of all trials discussed see Table 1).37 Both were more efficacious than placebo in the effect on abdominal pain, according to the US Food and Drug Administration (FDA)-recommended end point for abdominal pain in IBS with constipation, consisting of a ≥30% improvement from baseline for ≥50% of weeks. However, delayed-release forms of linaclotide, developed based on the premise that ileocecal delivery of the drug targets abdominal pain without affecting bowel habit, were not superior to placebo over most abdominal pain measures in a phase II RCT.38

Treatment studiedConditionNo. of studiesNo. of patientsComparatorReported effect

Linaclotide, 290 μg q.d.	IBS-C	3 RCTs summarized in a meta-analysis37	2447	Placebo	RR of abdominal pain persistence = 0.79 (95% CI, 0.73–0.85)
Plecanatide, 6 mg or 3 mg q.d.	IBS-C	2 RCTs summarized in a meta-analysis37	2194	Placebo	RR of abdominal pain persistence = 0.84 (95% CI, 0.78–0.90) and 0.87 (95% CI, 0.81–0.93), respectively
Loperamide	IBS-D Unselected patients with IBS	2 RCTs54,55	24 60	Placebo Placebo	Abdominal pain score 3.0 vs −0.14, P < .05 2.2 days with abdominal pain vs 8.3 days, P < .01
Eluxadoline, 100 mg or 75 mg b.i.d.	IBS-D	4 RCTs summarized in a meta-analysis56	2758	Placebo	RR of abdominal pain persistence = 0.89 (95% CI, 0.83–0.96) and 0.95 (95% CI, 0.88–1.04), respectively
Psyllium (up to 10 g/d)	Unselected patients with IBS	2 RCTs89,90	80 178	Placebo Placebo	Abdominal pain mild or absent in 52.5% vs 57.5%, N/S RR of adequate relief of abdominal pain at 1, 2, and 3 months = 1.60 (95% CI, 1.13–2.26), 1.44 (95% CI, 1.02–2.06), and 1.36 (95% CI, 0.90–2.04), respectively
Bran (up to 10 g/d)	Unselected patients with IBS	1 RCT90	190	Placebo	RR of adequate relief of abdominal pain at 1, 2, and 3 months = 1.13 (95% CI, 0.81–1.58), 1.22 (95% CI, 0.86–1.72), and 1.70 (95% CI, 1.12–2.57), respectively
Low FODMAP diet	IBS IBD	12 RCTs summarized in a meta-analysis91 2 RCTs92,93	914 52 89	BDA dietary advice Habitual diet Sham diet Sham diet Habitual diet	RR of abdominal pain persistence = 0.78 (95% CI, 0.57–1.06) RR of abdominal pain persistence = 0.72 (95% CI, 0.47–1.10) RR of abdominal pain persistence = 0.51 (95% CI, 0.30–0.87) Abdominal pain severity score 22 vs 30, P = .098 and 36 days with abdominal pain vs 38 days, P = .78 OR for improvement in abdominal pain frequency = 2.97 (95% CI, 1.12–7.89)
Rifaximin, 550 mg t.i.d. for 2 weeks	Nonconstipated IBS	2 RCTs summarized in a meta-analysis56	1260	Placebo	RR of abdominal pain persistence = 0.95 (95% CI, 0.89–1.01
FMT	IBS with bloating Unselected patients with IBS UC	2 RCTs96,97 1 RCT98	62 165 20	Placebo Placebo Usual treatment	Abdominal pain score 2.80 vs 3.88 at baseline with FMT, P = .001, compared with 3.57 vs 3.79 at baseline with usual treatment, P = .205 Abdominal pain score 166.8 and 186.3 posttreatment with 60 mg and 30 mg FMT, respectively, vs 307.0 with placebo, P < .001 Abdominal pain score 0.9 vs 4.5 at baseline with FMT, P = .026, compared with 1.8 vs 4.9 at baseline with usual treatment, N/S
Gelsectan	IBS-D	1 RCT99	60	Placebo	Number of patients with totally to slightly unacceptable abdominal pain reduced from 67% at baseline to 0% at 4 weeks with gelsectan vs 83% to 60% with placebo, statistical significance not reported
Probiotics Combination probiotics Lactobacillus-containing strains Saccharomyces cerevisiae I-3856 Bifidobacterium-containing strains Bacillus-containing strains	All in unselected patients with IBS	32 RCTs100 11 RCTs100 5 RCTs100 3 RCTs100 3 RCTs100	3469 1183 1482 389 212	Placebo Placebo Placebo Placebo Placebo	RR of abdominal pain persistence = 0.72 (95% CI, 0.64–0.82) RR of abdominal pain persistence = 0.59 (95% CI, 0.45–0.76) RR of abdominal pain persistence = 0.64 (95% CI, 0.45–0.90) RR of abdominal pain persistence = 0.78 (95% CI, 0.64–0.95) RR of abdominal pain persistence = 0.33 (95% CI, 0.23–0.47)
Ketotifen (titrated from 2 mg to 6 mg b.i.d.)	Unselected patients with IBS	1 RCT109	60	Placebo	7% of patients reporting severe abdominal pain vs 28%, P = .02
Ebastine 20 mg o.d.	Unselected patients with IBS Nonconstipated IBS	1 RCT110 1 RCT111	55 202	Placebo Placebo	Relief of abdominal pain in 41% vs 20%, P = .19 ≥30% improvement in abdominal pain in 37% vs 25%, P = .081
Disodium cromoglycate, 600 mg/d	IBS-D	1 RCT112	43	No treatment	≥50% improvement in abdominal pain in 77% vs 28%, P = .002
Peppermint oil (usually 2 capsules t.i.d.)	Unselected patients with IBS	7 RCTs summarized in a meta-analysis119	748	Placebo	RR of abdominal pain persistence = 0.76 (95% CI, 0.62–0.93)
Red pepper (capsaicin)	Unselected patients with IBS FD	1 RCT120 1 RCT121	50 30	Placebo Placebo	Abdominal pain score 1.9 vs 2.7 at baseline with red pepper, compared with 2.3 vs 2.4 at baseline with placebo, reported as “statistically significant” Abdominal pain score 1.61 posttreatment vs 2.37, P < .05
Alosetron, 1 mg b.i.d.	IBS-D	6 RCTs summarized in a meta-analysis56	2606	Placebo	RR of abdominal pain persistence = 0.83 (95% 0.78–0.88)
Ramosetron, 5 μg or 2.5 μg o.d.	IBS-D	5 RCTs summarized in a meta-analysis56	1928	Placebo	RR of abdominal pain persistence = 0.82 (95% CI, 0.75–0.89) and 0.75 (95% CI, 0.65–0.85), respectively
Ondansetron, 12 mg q.d, bimodal release or titrated up or down from 4 mg o.d.	IBS-D	3 RCTs summarized in a meta-analysis127	327	Placebo	RR of abdominal pain persistence = 0.95 (95% CI, 0.74–1.20)
Tegaserod, 6 mg b.i.d.	IBS-C FD	Pooled analysis of 4 RCTs128 2 RCTs129	2886 1360 1307	Placebo Placebo Placebo	OR for abdominal pain response = 1.38 (95% CI, 1.14–1.67) Abdominal pain response rate 44.9% vs 40.0%, P = .027 Abdominal pain response rate 44.0% vs 42.3%, P = .51
SSRIs (eg, escitalopram, 10 mg o.d.)	Unselected patients with IBS FD	5 RCTs summarized in a meta-analysis132 1 RCT133	262 195	Placebo Placebo	RR of abdominal pain persistence = 0.82 (95% CI, 0.58–1.16) Upper abdominal pain score 1.4 posttreatment vs 1.2, N/S
TCAs (eg, amitriptyline, 10–30 mg o.d., or imipramine, 50 mg o.d.)	Unselected patients with IBS FD	4 RCTs summarized in a meta-analysis132 1 RCT134 2 RCTs133,135	171 463 194 107	Placebo Placebo Placebo Placebo	RR of abdominal pain persistence = 0.53 (95% CI, 0.34–0.83) OR for ≥30% improvement in abdominal pain = 1.66 (95% CI, 1.12–2.46) Upper abdominal pain score 1.1 post-treatment vs 1.2, N/S Epigastric pain score 0.96 vs 1.24 at baseline with imipramine, P = .026, compared with 0.96 vs 1.13 at baseline with placebo, P = .13
SNRIs (eg., venlafaxine 150 mg o.d.)	Unselected patients with IBS	1 RCT136	30	Placebo	Frequency of abdominal pain or discomfort score 3.87 vs 4.93, P = .03
Oloroinab, 10 mg to 100 mg t.i.d.	IBS with abdominal pain Crohn’s disease with abdominal pain	1 RCT147 1 randomized, open-label study148	273 14	Placebo N/A	56.5%, 59.7%, and 56.7% of 10 mg, 25 mg, and 50 mg t.i.d., respectively, achieved a ≥30% improvement in abdominal pain vs 52.9% with placebo, N/S
					Change in abdominal pain score from baseline of −4.61 with 25 mg t.i.d. and −4.57 with 100 mg t.i.d.
Pregabalin, 75 mg o.d., or titrated up from 75 mg b.i.d.	Unselected patients with IBS FD	1 RCT154 1 RCT155	85 72	Placebo Placebo	Abdominal pain score 28 posttreatment vs 40, P = .008 Epigastric pain score 3.0 posttreatment vs 4.0, P = .01

Table 1

Summary of Evidence for Efficacy of Available Treatments Directed Against Peripheral Mechanisms of Abdominal Pain in Their Effect on Abdominal Pain as an End Point

BDA, British Dietetic Association; b.i.d., twice daily; CI, confidence interval; IBS-C, IBS with constipation; N/A, not applicable; N/S, not significant; o.d., once daily; OR, odds ratio; q.d., once daily; RR, relative risk; t.i.d., 3 times daily.

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Peripherally Acting Opioids and Visceral PainPharmacology and preclinical studies

Opioids signal through 4 GPCRs: μ-opioid receptors (MORs), δ-opioid receptors (DORs), κ-opioid receptors (KORs), and nociceptin opioid receptors.39 The analgesic effect of conventional opioids can be strong (eg, oxycodone, morphine) or weak (eg, codeine) and predominantly result from activation of MORs, although DORs and KORs also play a role. On nociceptors, these receptors trigger GPCR-Gi/o protein signaling leading to the recruitment of multifunctional intracellular proteins, called β-arrestins, and sustained signaling by endosomes.40 This signaling modulates ion channels and, ultimately, inhibits action potential firing. Receptor expression‎ is increased in inflammatory conditions, including active IBD, possibly leading to altered signaling.41

Conventional opioids can exhibit potent analgesic actions, particularly for acute pain, but are limited by their adverse effect profile, including cognitive impairment, respiratory depression, nausea, constipation, and addictive potential.42 Analgesic tolerance leads to dose escalation and consequently greater risk of these potentially life-threatening adverse effects. Dose escalation is also implicated in the development of a paradoxical switch in signaling, leading to opioid-induced hyperalgesia, a poorly understood condition.43 The opioid crisis has hastened the search for safer alternatives, including peripherally restricted opioids that lack addictive potential and central adverse effects such as respiratory depression and cognitive impairment.

Strategies to develop peripherally acting opioids are being explored to identify safe, yet effective, analgesics for visceral pain. Access to the central nervous system can be restricted, for example, by creating charged molecules, and several compounds display peripheral analgesic actions,44,45 including loperamide, a MOR agonist.46 To date, however, these do not exhibit sufficient analgesic effects to be clinically useful to treat visceral pain.

Another strategy is to target opioid receptor heterodimers, such as eluxadoline,47 a MOR agonist and DOR antagonist with weak affinity for KORs. MORs and DORs are coexpressed on nociceptors innervating the intestine, and eluxadoline shows high binding affinity for MOR/DOR heterodimers in cell assays48 and functional interaction between receptors. However, there has been sparse mechanistic study in whole-animal models to clarify the role of this interaction further.49

There are other promising strategies to develop safe opiates, such as enhancing endogenous opioids (eg, enkephalinase inhibitors), by developing pH-sensitive opioid analogues,50 which are only active at sites of inflammation and thus lack the adverse effect profile and addictive potential of conventional opioids. Combinations of subthreshold opioids and cannabinoid receptor 1 (CB1) agonists can provide strong analgesia51 without adverse effects. Novel delivery systems using nanoparticles of between 1 and 100 nm in diameter, containing opioid cargoes,52 target intracellular signaling in endosomes and can be delivered intrarectally to act locally within the inflamed colon. To date, most of these strategies are based on preclinical studies and none have been tested adequately in humans. Finally, female rodents are less sensitive to opiate analgesia,53 and whether these strategies have sex-specific effects would be important to eval‎uate.

Clinical trials

Few trials have been conducted with new opioid-related drugs in visceral pain, largely due to the negative impact of the opioid crisis. Despite widespread use of loperamide in clinical practice, there is little evidence for this. One 13-week RCT, recruiting patients with IBS with diarrhea (IBS-D), reported pain scores were significantly lower with loperamide.54 In a second 3-week trial that recruited IBS of all subtypes, the number of painful days was reduced significantly with loperamide, but only in patients with alternating bowel habit.55 Both trials used historical definitions of IBS, did not conform to guidance for design of treatment trials in DGBI, and many participants did not report abdominal pain at all. More rigorous trials of loperamide are needed, although it is unlikely these will ever be conducted.

In contrast, eluxadoline has been tested rigorously in phase III RCTs at 2 doses, 75 mg or 100 mg twice daily, with data pooled in a prior meta-analysis.56 Only 100 mg twice daily was superior to placebo for the FDA-recommended end point for abdominal pain, but benefit was modest. In addition, there have been safety issues, with episodes of acute pancreatitis and sphincter of Oddi dysfunction reported.

The Microbiome and Visceral PainAdvances in pathophysiology

The involvement of gut microbiota in the development of visceral pain is largely based on preclinical studies measuring pain thresholds after transfer of human stool microbiota into germ-free rodents or administration of live biotherapeutics (probiotics) or antibiotics, or both, in rodent models. For instance, germ-free rats colonized with stool microbiota from individuals with IBS display decreased pain thresholds in response to rectal distention.57 Further insights have been gained from studies involving gnotobiotic mice, revealing the role of commensal microbes in maintaining normal excitability of gut intrinsic neurons.58

Perturbing the gut microbiome during early life using vancomycin leads to visceral hypersensitivity in rats.59 Conversely, administration of live biotherapeutics, such as Faecalibacterium prausnitzii, Lactobacillus paracasei NCC2461, or Lactobacillus GG, reduces visceral hypersensitivity and intestinal permeability in preclinical models that alter the early-life microbiome.60,61 Unlike in early life, antibiotic administration improves visceral hypersensitivity in adult mice,62 suggesting potential age-dependent effects of the microbiome.

Interestingly, visceral pain responses to colorectal distention vary across the estrous cycle in female mice, but this effect is lost in germ-free animals. Ovariectomy caused visceral hypersensitivity in specific pathogen-free, but not germ-free mice, suggesting an interaction between sex hormones, visceral pain, and the microbiome.63

Building on insights from animal models, human studies exploring fecal microbiome changes in patients with IBS have found specific taxa that positively (Proteobacteria)64 or negatively (Bifidobacterium spp) correlate with the severity of pain.65 Although human microbiome studies have focused largely on the colon, changes in small-intestinal microbial composition, rather than bacterial numbers, appear to differentiate patients with abdominal pain from healthy controls.66 However, the role of small-intestinal microbiota in the pathophysiology of abdominal pain remains unclear. Together, although findings from preclinical models and human studies underscore a role of the gut microbiome, whether these changes are causal to the development of visceral hypersensitivity or a consequence of changes in diet and gastrointestinal motility is unknown.

Gut microbiota-derived metabolites, neurotransmitters, toxins, and cell wall components have emerged as potential factors underlying the pathophysiology of visceral hypersensitivity. These bioactive compounds can (1) sensitize sensory neurons indirectly by stimulating either enteroendocrine cells, which release serotonin, or immune cells, which release chemokines and cytokines, both of which act on distinct neuronal populations, (2) disrupt the intestinal barrier, allowing passage of potentially noxious stimuli, and (3) activate sensory neurons directly, particularly in instances where barrier function is compromised (Figure 2). Most bacteria-derived compounds are pleiotropic, acting via multiple signaling pathways. Thus, they exert wide-ranging effects. Furthermore, gut microbiota can both synthesize and use neurotransmitters, encompassing excitatory, such as glutamate, histamine, dopamine, and norepinephrine, and inhibitory neurotransmitters, such as γ-aminobutyric acid (GABA).67 These neurotransmitters allow intercommunication among microbiota members and the host.

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Figure 2 Mechanisms underlying gut microbiome-driven visceral nociception. Gut microbiome-derived products can sensitize peripheral nociceptors directly or act indirectly by stimulating immune cells or enterochromaffin cells, or both, to release cytokines, chemokines, or serotonin, or a combination of these, respectively. The gut microbiome can also modulate intestinal barrier function by altering the luminal bile acid and protease pool or through metabolites such as butyrate. AHR, aryl hydrocarbon receptor; CA, carboxylic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; FFAR, free fatty acid receptor; FXR, farnesoid X receptor; GPR35, G protein-coupled receptor 35; LCA, lithocholic acid; LPS, lipopolysaccharide; LTS, leukotrienes PAMPs, pathogen-associated molecular patterns; PAR2, protease activated receptor 2; PGN, peptidoglycan; TGR5, Takeda G protein-coupled receptor 5; TLR, Toll-like receptor.

Enterochromaffin cells are the primary cell type responsible for peripheral serotonin production. They are polymodal chemosensors, capable of detecting specific luminal signals via an array of receptor pathways and translating them to the enteric nervous system by modulating serotonin-sensitive primary afferent nerves.68 Catecholamine neurotransmitters, such as norepinephrine and dopamine, initiate the adrenoceptor alpha 2A (Adrα2A) and the transient receptor potential cation channel subfamily C member 4 (TRPC4) signaling cascade.

On the other hand, short-chain fatty acids (SCFAs) and branched-chain fatty acids, such as isovaleric acid and, to a lesser extent, butyrate, activate the olfactory receptor 558 and P/Q type Cav channel within enterochromaffin cells.68 A multitude of bacterial metabolites, including butyrate, also augment serotonin synthesis within enterochromaffin cells.69 The role played by serotonin in modulating visceral pain, as well as the critical role of enterochromaffin cells in isovalerate-induced visceral hypersensitivity, is discussed further below.

Pathogen-associated molecular pattern molecules, which include bacterial cell wall components such as lipopolysaccharide, bind to pattern recognition receptors such as Toll-like receptors, are present on immune cells and sensory neurons. Pathogen-associated molecular pattern molecules contribute to visceral hypersensitivity by influencing nociceptors directly or by affecting immune cells indirectly, leading to peripheral sensitization.70,71 Diet-derived metabolites from bacterial fermentation, such as SCFAs, indole and indole derivatives, and kynurenine, also modulate visceral nociception. Butyrate exerts antinociceptive effects72 via peroxisome proliferator-activated receptors suppressing the activity of nuclear factor κ-light-chain-enhancer of activated B cells, involved in pain and inflammation.73,74

Butyrate also augments intestinal barrier function via activation of hypoxia inducible factor,75 regulates immune cells via free fatty acid 2/3 receptors,76 and drives epigenetic changes. Tryptophan is converted by microbes to kynurenic acid77 or to indole derivatives,78 both of which exert anti-inflammatory effects via G protein-coupled receptor 35 and aryl hydrocarbon receptor, respectively,79,80

Gut bacteria play an important role in determining the luminal bile acid and protease pool. Bile acid metabolites, including deoxycholic acid, regulate pain through the activation of G protein-coupled bile acid receptor 1, and are present in both primary sensory neurons and macrophages. Proteases contribute to visceral hypersensitivity by targeting intestinal barrier function81 as well as by signaling directly through protease activated receptor 2, present on neurons.82 The luminal protease pool depends on the balance between bacterial proteases83 and suppression of host proteases by bacteria harboring β-glucuronidases.81

The identification of distinct microbiota-driven mechanisms opens the door for novel therapeutic strategies. Currently, microbiota-targeted interventions largely focus on augmenting intestinal barrier function. In preclinical studies, fiber maintained both microbial diversity and barrier function,84 and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) was found to preserve barrier function by decreasing lipopolysaccharide-mediated mast cell activation.85

Clinical trials

There are a multitude of methods to manipulate the microbiome, and thereby microbial metabolites, as a means of treating abdominal pain. SCFA enemas have been studied in IBD, but trials have not reported an effect on abdominal pain.86–88 Fiber has been assessed in IBS, but few trials report abdominal pain outcomes.89,90 One 12-week RCT found there was no benefit of psyllium, a soluble fiber, over placebo,89 but in another trial of psyllium, bran, or placebo, significant improvements in abdominal pain occurred with both psyllium and bran at several time points.90

A network meta-analysis of 12 trials studied the effect of a low FODMAP diet on abdominal pain.91 It was superior to a sham diet but was not superior to standard British Dietetic Association dietary advice for IBS or habitual diet. In contrast, in a RCT comparing a 4-week low FODMAP diet with a sham diet in patients with quiescent IBD with persistent gastrointestinal symptoms, abdominal pain severity and days with abdominal pain did not differ.92 In another 6-week trial of a low FODMAP diet vs normal diet in patients with IBD in remission with ongoing gastrointestinal symptoms, response for abdominal pain frequency, but not severity, was significantly higher with the low FODMAP diet.93 Abdominal pain response rates with rifaximin, a minimally absorbed antibiotic, according to the FDA-recommended end point, were reported in a meta-analysis.56 There was no benefit with rifaximin over placebo.

Although there have been multiple RCTs of fecal microbial transplant (FMT) in both IBS and IBD, summarized in prior meta-analyses,94,95 few report impact of FMT on abdominal pain. Two RCTs of FMT in IBS studied this end point.96,97 One 12-week trial of a single FMT via nasojejunal tube in IBS with predominant bloating reported abdominal pain scores were significantly reduced.96 In the second RCT, 30 mg or 60 mg of a single FMT via gastroscopy led to a significant reduction in abdominal pain at 3 months vs placebo.97 One RCT comparing FMT with usual therapy in active ulcerative colitis reported abdominal pain scores improved significantly with FMT at 2 weeks compared with baseline, but also improved significantly in the usual therapy arm.98

Gelsectan, a prebiotic with mucoprotective and bifidogenic effects, which may reinforce the intestinal barrier, was studied in 1 crossover trial.99 The number of participants with totally to slightly unacceptable abdominal pain was reduced from baseline to 4 weeks compared with placebo. Finally, in a meta-analysis certain combinations of probiotics, Lactobacillus-containing strains, Saccharomyces cerevisiae I-3856, and Bifidobacteria- and Bacillus-containing strains improved abdominal pain, but certainty in the evidence was low to very low across the studies, with heterogeneity between individual trials in most analyses.100

Histamine and Visceral PainPharmacology and preclinical studies

Histamine functions as a paracrine signaling molecule that can activate nociceptors in the gastrointestinal tract (Figure 3). It is a member of the biogenic amine family and is synthesized from l-histidine exclusively by l-histidine decarboxylase.101 Histamine signaling to nociceptors in the gut could originate from 2 sources: intestinal tissue or the lumen. In tissue, it is stored in high concentrations, predominantly in mast cells, but also in basophils and eosinophils. However, other cells in the gut also express histidine decarboxylase, including macrophages, neutrophils, platelets, and dendritic cells, and can synthesize and release histamine but do not store it.102 In the lumen of the gastrointestinal tract, there are 3 possible sources: synthesis by microbiota, ingestion of histamine-rich foods, and histamine released from tissues that permeates into the lumen.

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Figure 3 Novel mechanisms causing increased histamine signaling to intestinal nociceptors. (A) This schema shows that after combined food antigen (red triangle) and acute self-limiting colitis or combined food antigen and psychological stress exposure, reexposure to food antigen alone triggers increased IgE release within the intestine (which is not systemic), causing mast cell degranulation within the intestinal wall. The ensuing histamine release causes nociceptor sensitization and increased pain signaling. (B) This schema shows that ingestion of poorly absorbed complex carbohydrates (CHO) (eg, FODMAPs) can stimulate microbial production of histamine. Patients with Klebsiella aerogenes produce up to 100 times more histamine than those lacking this bacterium in their stool samples. Luminal histamine stimulates H4 and H1 receptors, leading to mast cell degranulation with ensuing nociceptor sensitization and increased pain signaling. DRG, dorsal root ganglia.

Histamine is metabolized by 2 dominant pathways, histamine-N-methyltransferase and diamine oxidase,103 resulting in N-methyl histamine and imidazole acetaldehyde metabolites, respectively. These metabolites also exhibit biological activity (eg, N-methyl histamine), and the preponderance of the pathways may differ between mast cells and microbiota.

Histamine, and possibly some metabolites, can activate 4 GPCRs, H1 to H4.101 These GPCRs signal intracellularly via Gq and cyclic adenosine monophosphate to modulate passive and voltage-gated ion channels on nociceptors and other effector pathways in nonneuronal cells. The distribution of these receptors within the gut suggests histamine activates pain signaling directly through activation of neurons and indirectly via immune cell activation (Figure 3).

In humans,104 H1 receptors are found on connective tissues cells, immune cells, enterocytes, smooth muscle cells, and nerves, H2 receptors are found on gastric parietal cells, enterocytes, immunocytes, enteric nerves, and smooth muscle cells, and H4 receptors are expressed on immune cells, blood vessels, nerves, and enterocytes. H3 receptors have yet to be identified in humans.

Previous studies highlight the role of histamine in patients with IBS, demonstrating increased levels of histamine (and proteases) in mucosal biopsy specimens from patients compared with healthy controls, evidence of mast cell activation, and the ability of histamine in tissue supernatants from patients to exaggerate activation of rodent and human nociceptive neurons.105 Sex differences have not been described. More recent studies show increases in duodenal eosinophils in patients with FD, another source of tissue histamine, implicating a role in abdominal pain in this disorder.106 The triggers resulting in abnormal mast cell-histamine signaling observed in these patients have been unclear, but recent preclinical studies suggest multiple possible etiologies, as outlined below.

When mice develop a self-limiting bacterial colitis and are exposed simultaneously to a food antigen, and then reexposed to the food antigen alone after resolution of infection, they lose oral tolerance to the food antigen.14 This leads to visceral hypersensitivity and mast cell activation with histamine release. This exaggerated pain signaling was blocked by an H1 receptor antagonist, which inhibits histamine signaling to neurons, and by an IgE antibody, which prevents mast cell activation. Tissues exhibited elevated IgE levels, consistent with loss of oral tolerance, but there was no systemic increase in IgE, highlighting immune activation was confined to the intestine.

Injection of common antigens into the rectal mucosa in patients with IBS caused greater wheal and flare responses, compared with healthy volunteers, consistent with the hypothesis that some patients with IBS are sensitized to food antigens.14 Recent preliminary studies suggest psychological stress can also induce loss of oral tolerance to food antigens and lead to mast cell-histamine–mediated visceral hypersensitivity in both the small intestine and colon, a feature observed in many patients with IBS.107

Histamine production by the microbiota may be stimulated by poorly absorbed complex carbohydrates. In a study using germ-free mice to create a humanized IBS mouse model with fecal microbiota from patients with IBS and healthy controls,108 mice given fecal samples from patients with IBS who were high histamine producers, based on stool and urine samples, exhibited visceral hyperalgesia. This exaggerated pain signaling was blocked by H1- and H4- receptor antagonists, suggesting several signaling pathways were involved (Figure 3). Some of the histamine in the luminal samples could originate from the host (eg, mast cell degranulation). However, high histamine producers were found to have microbial species, including Klebsiella aerogenes, in their stool that could make up to 100 times more histamine than those without.

Clinical trials

Drugs targeting histamine receptors or stabilizing mast cells have not been well studied in gastrointestinal diseases. An 8-week trial of ketotifen, a H1-receptor antagonist, in IBS reported a significant improvement in abdominal pain over placebo.109 Ebastine, another H1-receptor antagonist, has been assessed in IBS.110,111 A 12-week proof-of-concept RCT found rates of relief of abdominal pain were numerically higher with ebastine, but not significantly so. In a subsequent phase IIb placebo-controlled trial, rates of abdominal pain improvement were higher with ebastine, although this was not significant.111 The effect of the mast cell stabilizer disodium cromoglycate on abdominal pain was studied in a RCT in IBS-D.112 In this 6-month study, compared with no treatment, significantly more patients randomized to disodium cromoglycate experienced abdominal pain improvement.

Transient Receptor Potential Vanilloid 1 and Visceral PainPharmacology and preclinical studies

TRPV1 is a nxxxxonselective ligand-gated cation channel that is highly enriched in gastrointestinal tract nociceptors. It is activated by polymodal stimuli, including mechanical stretch, noxious heat, low pH, exogenous chemical irritants, such as capsaicin (the active ingredient in chili peppers), and endogenous lipid metabolites of arachidonic acid (eg, the endocannabinoid anandamide113). Selective ablation of colon-projecting TRPV1-expressing neurons decreased nociception in response to colorectal distention in mice,22 highlighting its critical role in visceral pain. Estrogens can modulate lumbosacral dorsal root ganglia TRPV1 expression‎, suggesting a potential mechanism for sex differences in visceral pain.114

Sensitization of TRPV1 by inflammatory mediators, such as histamine,110 is one of the key pathways in mediating peripheral visceral hypersensitivity, as discussed above. However, TRPV1 expression‎ does not necessarily correlate with receptor sensitization. For example, in patients with IBS who were hypersensitive to rectal distention, rectal application of capsaicin caused increased pain perception. No change in TRPV1 expression‎ was noted when comparing hypersensitive and normosensitive patients with IBS, suggesting that although TRPV1 expression‎ is important, additional factors, such as receptor sensitization or central factors, or both, are necessary in mediating visceral pain.115

Although most of the studies have focused on TRPV1 sensitization in IBS and FD,113 TRPV1 may also play a role in chronic visceral pain in patients with IBD in remission. Rectal TRPV1 expression‎ was increased in patients with IBD in endoscopic remission with chronic visceral pain and correlated with patient-reported symptoms.116 Visceral hyperalgesia was TRPV1-dependent in postinflammatory mice,117 and they also displayed increased SCFA-producing microbiota and stool SCFA content. These microbial-derived SCFAs increased capsaicin-evoked calcium responses in the postinflammatory state, suggesting that microbial metabolites can sensitize TRPV1.118

Clinical trials

Peppermint oil, as well as being a smooth muscle relaxant, may have effects on TRPV1 signaling. A meta-analysis showed it was more efficacious than placebo for abdominal pain.119 However, benefit was modest, with heterogeneity between studies, and most trials did not use FDA-recommended end points. Although capsaicin stimulates the TRPV1 receptor, leading to worsening abdominal pain, repeated administration down-regulates the receptor. A 6-week trial in IBS showed abdominal pain scores were significantly lower, compared with baseline, in patients receiving red pepper pills compared with those receiving placebo.120 A similar 5-week study in FD demonstrated a significant reduction in epigastric pain scores with red pepper vs placebo.121 However, patients in both trials randomized to red pepper dropped out due to pain exacerbations.

Serotonin (5-Hydroxytryptamine) and Visceral PainPharmacology and preclinical studies

The monoamine neurotransmitter 5-hydroxytryptamine (5HT) plays an integral role in initiation of intrinsic gut reflexes regulating motility, secretion, and vasodilation. It also participates in the pathogenesis of visceral pain via afferent nerve 5-HT3 and 5-HT4 receptors; drugs that modulate these receptors have been used extensively in the treatment of visceral hypersensitivity.122 The actions of 5HT are terminated by the serotonin selective reuptake transporter, a peripheral target of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and serotonin norepinephrine reuptake inhibitors122 (SNRIs).

Genetic polymorphisms in the 5-HT3 receptor and the serotonergic synthetic enzyme, tryptophan hydroxylase, are associated with increased IBS susceptibility, whereas SSRI transporter polymorphisms are associated with both IBS and FD.123 Multiple studies report changes in 5HT synthesis, reuptake, and release in IBS,124 suggesting dysregulated 5HT signaling contributes to the pathophysiology of visceral pain. Surprisingly, few studies eval‎uating the role of TCAs in visceral pain have been performed in rodent models.

Although 5HT can be secreted by enteric neurons and mucosal mast cells, most of the body’s 5HT is synthesized and stored by enterochromaffin cells.122 Enterochromaffin cells are electrically excitable, and display axon-like basal processes, forming functional connections with extrinsic and intrinsic afferent neurons, termed neuropods.68,125 Enterochromaffin cells function as luminal sensory transducers, releasing 5HT in response to dietary nutrients and microbial products, as well as mucosal distortion via mechanosensitive Piezo-02 channels.126 5HT release by enterochromaffin cells, thus initiates intrinsic gut reflexes and stimulates extrinsic nerves.

A recent study eval‎uated the role of a mucosal afferent-enterochromaffin cell circuit in the pathogenesis of visceral hypersensitivity using transgenic mice,26 where enterochromaffin cells could be activated or silenced selectively. Direct activation of enterochromaffin cells elicited 5HT release and was sufficient to cause both acute and chronic visceral hypersensitivity to colorectal distention. Remarkably, activation of enterochromaffin cells was sufficient to elicit anxiety-like behavior in mice. These effects were inhibited by the 5HT3 antagonist alosetron, which decreased mucosal afferent activity. Conversely, silencing activity of enterochromaffin cells attenuated 5HT release and visceral hypersensitivity mediated by the microbial metabolite, isovalerate, in male mice. The mucosal afferent-enterochromaffin cell circuit demonstrated high tonic activity in female, but not male, mice suggesting a sex-specific contribution to pain signaling. Together, these data demonstrate that the enterochromaffin cell-mucosal afferent circuit plays an essential role in pathogenesis of visceral hypersensitivity.26

It is possible that the GC-C pathway also regulates 5HT secretion from enterochromaffin cells. GC-C is expressed not only by enterocytes but also by a subtype of monoamine synthesis-expressing neuropods enriched in the proximal intestine of mice.36 GC-C enriched neuropods formed functional connections with nociceptors in cocultures and caused spontaneous nociceptor activation, which was abolished by linaclotide. The antinociceptive effects of linaclotide on the response to colorectal distention were lost in mice that were deficient in neuropod GC-C.36 Thus, it is possible that enterochromaffin GC-C activation regulates 5HT tone, but whether this mechanism is active in vivo is unclear.

Clinical trials

The efficacy of the 5HT3-receptor antagonists alosetron and ramosetron, according to the FDA-recommended end point for abdominal pain, has been reported in multiple trials in IBS-D, pooled in a meta-analysis.56 Ramosetron, 2.5 μg daily and 5 μm daily, and alosetron, 1 mg twice daily, were superior to placebo, although alosetron has been associated with ischemic colitis. Varying doses of ondansetron, another 5HT3-receptor antagonist with a long history of safety, were assessed in 3 trials in IBS-D, summarized in another meta-analysis.127 The drug was not superior to placebo for pain.

For 5HT4-receptor agonists, in a pooled analysis of data from 4 RCTs in IBS, tegaserod, 6 mg twice daily, was more efficacious for pain than placebo.128 In two 6-week trials of tegaserod in FD, 6 mg twice daily was superior to placebo for abdominal pain in 1 RCT but not the other.129 Safety issues arising from cardiovascular and cerebrovascular ischemic events led to the withdrawal of tegaserod. Although it was reintroduced briefly, tegaserod is now no longer available. Prucalopride was assessed in chronic constipation and was efficacious,130 but no RCTs report its efficacy in improving abdominal pain, and it has never been tested in IBS or FD.

Although SSRIs, TCAs, and SNRIs are antidepressants, in the context of treating abdominal pain, they act as gut-brain neuromodulators involving, at least in part, 5-HT131; discussion of the central actions of these compounds is beyond the scope of this review. SSRIs have been assessed in IBS and FD, with no impact on abdominal pain in IBS in a prior meta-analysis,132 and a reduction in pain scores in FD in a single RCT of escitalopram, 10 mg once daily, but with no benefit over placebo.133 TCAs, however, were more efficacious than placebo for abdominal pain in IBS in a meta-analysis of 4 RCTs132 and more recently in a 6-month trial in 463 patients.134 In one 12-week trial in refractory FD, imipramine led to a significant reduction in epigastric pain scores vs placebo,135 but another trial of amitriptyline demonstrated no benefit.133 The SNRI venlafaxine was assessed in a single 12-week RCT in IBS; abdominal pain frequency scores were reduced significantly compared with placebo.136 An RCT of FD did not report its effect on abdominal pain.137

Cannabinoids and Visceral PainPharmacology and preclinical studies

Cannabinoids are widely used alternative therapies to treat abdominal pain in both IBD and IBS.138,139 The actions of cannabinoids are mediated via the endocannabinoid system, which regulates gastrointestinal motility, secretion, immune function, intestinal permeability, and visceral hypersensitivity.140

The classical components of the endocannabinoid system are the endogenous cannabinoid ligands, anandamide, and 2-arachidonoylglycerol, as well as their biosynthetic and degradative enzymes. These are found throughout the microbiota-gut-brain axis, including the epithelium, enterochromaffin cells, enteric nervous system, and immune system, as well as extrinsic afferent nerves, where they primarily exert an antinociceptive effect. Anandamide is also an agonist at TRPV1. Thus, endocannabinoids have both pronociceptive and antinociceptive effects, depending on the receptor.140 Interestingly, commensal bacteria can produce endocannabinoid-like molecules,141 although whether a microbial source of endocannabinoid-like molecules plays a role in visceral hypersensitivity is unknown.

In animal models of stress-induced visceral hypersensitivity and in postinflammatory models, CB1 and CB2 agonists decrease the visceromotor response to colorectal distention.140,142–144 Endocannabinoids can either exert their antinociceptive actions directly via CB1 and CB2 receptors expressed on nociceptors142,145 or indirectly via down-regulation of mast cell or macrophage activation.140 However, clinical use of cannabinoids is hampered by psychotropic adverse effects. Accordingly, there has been interest in synthesizing peripherally restricted cannabinoid receptor agonists.142–144

A recent preclinical study of the peripherally restricted CB2 receptor agonist, olorinab, was performed in rodent models of acute colitis and postinflammatory visceral pain.142 Olorinab reversed the colitis-induced hypersensitivity to colorectal distention in both the acute and postinflammatory state; no effects on visceral pain were seen when olorinab was given to controls. Olorinab was able to decrease mechanosensitivity of ex vivo afferent nerves in a dose-dependent manner, both in acute colitis and in the postinflammatory state, although CB2 expression‎ was not up-regulated in afferent nerves compared with controls.142 Unfortunately, only male mice were eval‎uated in this study, although CB2 expression‎ is increased in female patients with IBS.146 These data suggest CB2 receptors on visceral afferents are sensitized by inflammation and, in turn, play a regulatory anti-nociceptive role.

Clinical trials

In a 12-week phase II dose-ranging study of olorinab in IBS, the proportion of patients experiencing improvement in abdominal pain was not significantly higher with any dose studied.147 However, in those with moderate to severe pain at baseline, abdominal pain scores were significantly improved with 50 mg 3 times daily. No placebo-controlled trials of this drug in IBD have been conducted, although an 8-week open-label randomized study recruiting patients with Crohn’s disease who reported abdominal pain found a significant reduction in pain scores from baseline with olorinab.148 There is no evidence for other drugs acting on cannabinoid receptors for treating abdominal pain in gastrointestinal disorders.149

γ-Aminobutyric Acid and Visceral PainPharmacology and preclinical studies

Functional GABA receptors have been identified in the nerve terminals of colonic afferents. The activation of GABA receptors (GABAA and GABAB) by endogenous GABA decreases sensitivity of colonic afferents, whereas GABAA activation also reduces visceral pain perception.150 Functional GABAergic transmission has also been found in nociceptors, producing strong analgesic effects.151 In addition to endogenous production, certain bacteria expressing glutamate decarboxylase, can produce GABA from glutamate.67 In rodent models, GABA-producing bacteria have an analgesic effect in stress-induced152 and fecal-retention153 models of visceral hypersensitivity.

Clinical trials

There has been 1 RCT of pregabalin in both FD and IBS, but no trials in other painful gastrointestinal disorders and no trials of gabapentin. Abdominal pain scores were significantly lower in patients assigned to titrated pregabalin vs placebo in a 12-week trial in IBS.154 Similarly, pregabalin, 75 mg daily, was superior to placebo for epigastric pain scores in an 8-week trial in FD.155

Conclusions

Chronic visceral pain represents a substantial burden to patients. Despite the potential for the evidence-based treatments described above, a need remains for the development of novel therapeutics to treat sensitization of peripheral pain pathways effectively. Future directions should include the identification of microbial vs host sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), similar to current work eval‎uating histamine (Figure 4).

Figure viewer

Figure 4 Areas for future investigation in peripheral mechanisms of visceral pain. There is a need to identify peripheral mechanisms underlying visceral pain and develop novel therapeutic agents to treat patients. Identification of microbial vs host sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), is one such mechanistic area. Eval‎uation of the relative contribution of each pathophysiologic mechanism to nociceptor sensitization in individual patients, and thus use of combination therapies targeting these mechanisms, is key. For opiates, some promising strategies for the development of safe yet effective opiate therapies are the development of pH-sensitive opiate analogues active at the site of inflammation, use of peripherally restricted agents or subthreshold combinations of opiates, and CB1 receptor agonists. Because chronic visceral pain is more common in women, future studies should eval‎uate whether pain mechanisms are sex-specific and whether treatments should be used in a sex-specific manner. ♀, female; ♂, male.

With respect to the microbiome, research should avoid observational-based community profiling and focus on mechanistic approaches eval‎uating how microbiota or microbial products, or both, interact with nociceptors. Methods to test the relative contribution of each pathophysiologic mechanism to the sensitization of peripheral nociceptors and their role in overlapping pain syndromes in individual patients is also required. This would allow the use of specific drug combinations to target multiple mechanisms synergistically.

Given the sex bias of chronic visceral pain, future studies should eval‎uate whether pain mechanisms are sex-specific or whether treatments should be used in a sex-specific manner. Identifying whether differing or similar peripheral mechanisms are involved in the development of chronic visceral pain in patients with IBD vs painful DGBI will be important. Finally, eval‎uation of the relative contribution of peripheral vs central sensitization to symptoms would be important to individualize patient therapy. Continued multidisciplinary collaboration between clinician-scientists and bench-based scientists with the use of innovative reverse translational approaches is necessary to advance this field, identify new target pathways, and improve the clinical management of patients.

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