삼차 신경통 원인, 예후, 만성통증 .. 문치연 치료법 최신 논문 탐구!!

[문형철]

Abstract

Trigeminal neuralgia (TN) is a facial pain disorder characterized by intense and paroxysmal pain that profoundly affects quality of life and presents complex challenges in diagnosis and treatment. TN can be categorized as classical, secondary and idiopathic. Epidemiological studies show variable incidence rates and an increased preval‎ence in women and in the elderly, with familial cases suggesting genetic factors. The pathophysiology of TN is multifactorial and involves genetic predisposition, anatomical changes, and neurophysiological factors, leading to hyperexcitable neuronal states, central sensitization and widespread neural plasticity changes. Neurovascular compression of the trigeminal root, which undergoes major morphological changes, and focal demyelination of primary trigeminal afferents are key aetiological factors in TN. Structural and functional brain imaging studies in patients with TN demonstrated abnormalities in brain regions responsible for pain modulation and emotional processing of pain. Treatment of TN involves a multifaceted approach that considers patient-specific factors, including the type of TN, with initial pharmacotherapy followed by surgical options if necessary. First-line pharmacological treatments include carbamazepine and oxcarbazepine. Surgical interventions, including microvascular decompression and percutaneous neuroablative procedures, can be considered at an early stage if pharmacotherapy is not sufficient for pain control or has intolerable adverse effects or contraindications.

삼차신경통(TN)은

얼굴에 발생하는 극심하고 발작적인 통증을 특징으로 하는 안면 통증 장애로,

삶의 질을 심각하게 저하시키며

진단과 치료에 복잡한 도전을 제시한다.

TN은

고전적(classical), 이차성(secondary), 특발성(idiopathic)으로 분류할 수 있다.

역학 연구에 따르면 발생률은 다양하며,

여성과 고령자에서 유병률이 높고,

가족성 사례는 유전적 요인을 시사한다.

TN의 병태생리는 다인자적이며,

유전적 소인, 해부학적 변화, 신경생리학적 요인이 관여하여

신경세포의 과흥분성 상태, 중추 감작, 그리고 광범위한 신경 가소성 변화를 초래한다.

삼차신경 근부의 신경혈관 압박(이 부위는 주요 형태학적 변화를 겪음)과

일차 삼차신경 구심성 섬유의 국소 탈수초는

TN의 핵심 병인이다.

TN 환자를 대상으로 한 구조적·기능적 뇌영상 연구에서는

통증 조절과 통증의 감정 처리에 관여하는 뇌 영역에서

이상이 확인되었다.

TN의 치료는

TN의 유형을 포함한 환자 개별 요인을 고려한 다각적 접근이 필요하며,

초기 약물 요법을 시행한 후 필요 시 수술적 옵션을 고려한다.

1차 약물 치료로는

카르바마제핀(carbamazepine)과 옥스카르바제핀(oxcarbazepine)이 사용된다.

약물 요법으로 통증 조절이 충분하지 않거나,

부작용이 심하거나 금기사항이 있는 경우에는

미세혈관 감압술(microvascular decompression)과

경피적 신경 파괴술(percutaneous neuroablative procedures) 등의 수술적 중재를 조기에 고려할 수 있다

삼차신경통(TN, douloureux)은

얼굴에 갑작스럽고 극심한 전기 충격 같은 발작성 통증을 특징으로 하는

만성 신경병증성 안면통증 장애입니다.

통증은

삼차신경의 하나 이상의 분포 영역에서 나타나며,

재발과 완화를 반복합니다.

역학 (Epidemiology)

• 발생률(Incidence): 연구마다 차이가 크며, 2.1~27건 / 10만 명·년
  • 1940년대~1980년대: 낮은 수치
  • 최근 연구: 4.3~5.5건 / 10만 명·년 정도로 보고
• 유병률(Preval‎ence): 평생 유병률 0.16% ~ 0.3%
• 연령: 고령자에서 급증 (50~60대에 가장 흔함)
• 성별: 여성에게 더 흔함 (여성:남성 ≈ 2:1 ~ 3:1)
• 기타: 도시 지역에서 더 높은 유병률 관찰

분류

• 고전적(Classical) TN: 신경혈관 압박이 원인
• 이차성(Secondary) TN: 다발성 경화증, 종양 등 명확한 원인 질환 존재
• 특발성(Idiopathic) TN: 원인을 명확히 찾을 수 없는 경우

주요 특징 및 영향

• 삶의 질을 가장 심각하게 저하시키는 통증 질환 중 하나
• 최근 TN에 대한 연구와 치료 기술이 빠르게 발전 중
• 새로운 치료 옵션(보톡스, 신경자극 등) 연구 활발

TN의 질병 부담 (Burden)

• TN은 극심한 통증으로 인해 환자의 일상생활·사회생활·경제적 활동에 큰 지장을 줍니다.
• 환자의 45%가 일상생활 수행이 불가능할 정도로 심각하며, 50% 이상이 6개월 이상 통증으로 고통받음.
• 경제적 부담: 불필요한 치과 치료, 반복된 약물 처방, 입원 치료 등으로 막대한 비용 발생.
• 치료 부담: 94%의 환자가 약물을 복용하지만, 많은 환자가 부작용으로 치료를 중단하거나 효과가 불충분함.
• 결과적으로 삶의 질이 크게 저하되고, 우울·불안 등 정신적 문제도 동반됨.

동반질환 (Comorbidities)

• 고혈압: TN 환자에서 상대적으로 더 흔함 (특히 고전적 TN).
• 정신과적 질환:
  • 우울증 19~50%
  • 불안장애 35~65%
• 다발성 경화증(Multiple Sclerosis) 환자에서는 TN 발생률이 20배 이상 높음.
• TN 환자는 다른 만성 통증 질환보다 동반질환이 많아 종합적인 관리가 필요.

3. 위험인자 (Risk Factors)

• 고령, 여성, 가족력
• 동맥경화증 (혈관 변화)
• 고혈압 및 기타 심혈관 위험인자
• TN 발병 위험을 높이는 요인으로 작용하며, 특히 신경혈관 압박을 유발할 가능성이 높음.

4. 병태생리 / 기전 (Mechanisms/Pathophysiology)

TN의 병태생리는 다인자적이며 아직 완전히 밝혀지지 않았습니다.

주요 기전은 다음과 같습니다:

• 신경혈관 압박 (Neurovascular Compression) → 가장 중요한 원인 (고전적 TN). 삼차신경 근부가 혈관에 눌려 국소 탈수초 발생.
• 신경 과흥분성 → 탈수초된 신경에서 이상신호(ectopic impulses) 발생 → 발작성 통증.
• 중추 감작 (Central Sensitization) → 삼차신경핵과 상위 중추(뇌)에서 통증 증폭.
• 기타 요인:
  • 유전적 요인 (특정 유전자 변이)
  • 염증 및 면역 반응
  • 해부학적 변화 (혈관 루프, 골성 변화 등)
  • 유발인자: 씹기, 말하기, 세수, 바람 등 가벼운 자극

TN의 3가지 유형과 원인



공통 병태생리 과정 (중심 기전)

1. 삼차신경 근부(Root Entry Zone) 축삭 탈수초 → 모든 TN 유형에서 핵심적인 변화
2. 주요 병리 변화
   • 이소성 충동 발생 & Ephaptic transmission (비정상적 신경 간 교차 흥분)
   • 염증 (국소 거미막염)
   • 축삭 소실 & 삼차신경 위축
3. 결과적으로 나타나는 현상
   • 중추 감작 (척수 삼차신경핵 → 시상 → 대뇌피질)
   • 탈수초화된 신경의 과흥분성
   • Deafferentation hypersensitivity (감각 탈실 → 과민성)

최종 통증 양상

• 발작성 신경통 통증 (Spontaneous and evoked neuralgic pain) ← 주로 stabbing pain
• 지속성 동반 통증 (Concomitant continuous pain)
  
  

그림은 삼차신경통의 통증이 어떻게 발생하고, 뇌에서 어떻게 처리되는지를 전체적으로 보여주는 모식도.

주요 내용은

말초(삼차신경) → 뇌간 → 시상 → 대뇌로 이어지는 통증 경로와,

TN에서 중요한 통증 조절 기전을 함께 표시한 것.

전체 구조

삼차신경절(Trigeminal ganglion): 통증 신호가 시작되는 곳

① 신경혈관 압박:

• SCA (상소뇌동맥), AICA (전하소뇌동맥), SPV (상소뇌정맥) 등이 삼차신경 근부를 누르는 모습 → 고전적 TN의 가장 흔한 원인

② 다발성 경화증 플라크: 뇌간이나 삼차신경로에 발생한 플라크 → 이차성 TN의 대표적 원인

③ 신경세포 과흥분: 탈수초된 축삭에서 발생하는 이소성 충동(ectopic firing)과 ephaptic transmission(신경 간 비정상적 교차 흥분)을 보여줌

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뇌 속 통증 전달 및 조절 경로

주요 통증 상승 경로 (빨간색 선)

1. 삼차신경 → 척수 삼차신경핵(Spinal trigeminal nucleus)
2. → 시상(Thalamus)
3. → 체성감각 피질(Somatosensory cortex ④) : 통증의 위치와 강도를 인식

통증 조절 및 감정 관련 경로 (파란색 선)

• 뇌간 통증 조절계 (Brainstem pain-modulating system)
• Periaqueductal grey (PAG): 내인성 진통 시스템의 핵심
• Rostral ventromedial medulla: 통증을 억제하거나 증폭
• 시상하부(Hypothalamus), 편도체(Amygdala): 자율신경 반응과 공포·불안 감정 처리
• 전대상피질(Anterior cingulate cortex), 전전두피질(Prefrontal cortex ⑤): 통증의 감정적·인지적 평가 (통증을 더 심하게 느끼게 하거나 조절)

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TN에서 중요한 점

• ⑤ 전두엽 영역 (Prefrontal & Anterior cingulate cortex): TN 환자에서 구조·기능 이상이 자주 관찰되는 부위로, 만성 통증의 감정적 고통과 통증 만성화에 핵심 역할을 합니다.
• 정상적으로는 파란색 경로가 통증을 억제하지만, TN에서는 중추 감작(central sensitization)으로 인해 통증 억제 기능이 떨어지고 오히려 증폭됩니다.
• 결과적으로 가벼운 자극(세수, 바람, 말하기 등)에도 극심한 발작성 통증이 발생합니다

Trigeminal ganglion cell (삼차신경절 세포)에서 시작된 신호가 압박(Compression) + 탈수초(Demyelination) → 이소성 충동 + Ephaptic transmission → 중추 감작(Central sensitization) → 대뇌피질까지 극심한 통증으로 전달됩니다.

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① 삼차신경절 수준 (Trigeminal ganglion cell)

• 다양한 이온채널이 관여:
  • TRPM (칼슘 관련)
  • Nav1.7, Nav1.3 (나트륨채널 — TN에서 특히 과활성화)
  • K+ 채널 (칼륨채널 — 정상적으로 억제 역할)
• 압박이나 다발성경화증으로 인한 탈수초가 발생하면 이온채널의 균형이 깨져 신경세포가 과흥분 상태가 됩니다.

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② 축삭(신경섬유) 수준 — 통증 신호 발생

• Nociceptive axon (C fiber): 실제 통증을 전달하는 섬유
• Non-nociceptive axon (Aδ fiber): 정상적으로는 가벼운 촉각 등을 전달

주요 이상 현상

• Ectopic impulse generation: 정상 자극 없이도 자발적으로 충동 발생 (발작성 통증의 핵심)
• Ephaptic transmission (교차 흥분): 손상된 신경 사이에 절연이 깨져, 한 신경의 신호가 다른 신경으로 직접 전달됨
• Cross-talk: 통증 섬유와 비통증 섬유 간 비정상적 신호 교환 → 가벼운 터치(세수, 바람)에도 극심한 통증 유발 (allodynia)

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③ 척수 삼차신경뉴런 수준 — 중추 감작

• High-frequency stimulation: 과도한 고빈도 신호가 지속적으로 들어옴
• 염증성 사이토카인 분비
• NMDA 수용체, AMPA 수용체 과활성화 → 칼슘 유입 증가
• NO (일산화질소) 생성 증가 → 통증 증폭
• 결과: 중추 감작(Central sensitization) 발생 → 통증이 더 강하고 오래 지속됨

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상위 중추로의 전달

• Spinal trigeminal neuron → Brainstem (RVM) → Thalamus → Cortex
• 이 과정에서 통증 조절 기능이 떨어지고, 감정·인지 영역까지 영향을 주어 만성 통증 + 우울·불안이 동반됩니다.

삼차신경 3대 분지

분지이름분포 영역통증 발생 빈도

V1	Ophthalmic branch (안신경)	이마, 눈 주위, 코 윗부분	4–33%
V2	Maxillary branch (상악신경)	뺨, 코, 윗입술, 윗잇몸	17–73% (가장 흔함)
V3	Mandibular branch (하악신경)	아랫입술, 아랫잇몸, 턱, 귀 앞	19–60%

통증이 여러 분지에 동시에 발생하는 경우

• V1 + V2 : 10%
• V2 + V3 : 20–38% (상당히 흔함)
• V1 + V2 + V3 : 1–13%
• 단일 분지만 : 대부분 V2 또는 V3

통증 발생 측면 (Laterality)

• 오른쪽 얼굴 : 56–70% ← 가장 흔함
• 왼쪽 얼굴 : 29–41%
• 양측 (Bilateral) : 1–3% (매우 드묾)

한눈에 보는 핵심 정리

• 가장 흔한 부위 → V2 (상악신경) 영역 (뺨 ~ 코 ~ 윗입술)
• 두 번째 → V3 (하악신경) 영역 (턱과 아랫입술)
• V1 (안신경)은 비교적 덜 흔하지만, 눈 주위 통증이 있으면 V1 침범을 의심
• 오른쪽 얼굴에 발생하는 경우가 왼쪽보다 거의 2배 가까이 많음
• 양쪽 얼굴에 동시에 오는 경우는 매우 드물다

1. 안면통증 장애 (Facial pain disorders)

• 지속성 특발성 안면통증 (Persistent idiopathic facial pain / Atypical facial pain): 지속적인 둔한 통증, 심리적 스트레스나 터치로 악화
• 외상 후 삼차신경병증 (Painful post-traumatic trigeminal neuropathy): 외상 후 발생, 지속적 통증 + 감각 이상 (저감각, 과감각)
• 대상포진 후 신경통 (Herpes zoster related): 수포 후 발생하는 지속적 타는 듯한 통증
• 설인두신경통 (Glossopharyngeal neuralgia): 혀 뒤, 인두, 귀 깊은 곳 통증 (삼키기, 기침, 하품 시 유발)
• 종양 (Tumours): 점차 악화되는 지속 통증 + 감각 이상

2. 치성(치아 관련) 장애 (Odontogenic disorders)

• 치아 균열/파절, 우식증(충치), 치수염: 씹을 때나 차가운/뜨거운 음식 섭취 시 유발되는 날카로운 통증
• 통증이 수분~수시간 지속될 수 있음

3. 기타 구강안면 통증 (Non-odontogenic orofacial pains)

• 측두하악관절 장애 (Temporomandibular disorders): 턱관절·귀·관자놀이 주변 둔한 통증, 씹거나 입 벌릴 때 악화, 턱 운동 장애 동반

4. 두통 장애 (Headache disorders)

• 단시간 신경양 두통 (Short-lasting unilateral neuralgiform headache): TN과 매우 비슷하지만 자율신경 증상(눈물, 코막힘 등) 동반
• 일차성 찌르는 두통 (Primary stabbing headache): 두피에 찌르는 통증, 자율신경 증상 없음
• 군발두통 (Cluster headache): 눈 주위·관자놀이 극심 통증 + 자율신경 증상, 15~180분 지속

1. 초기 평가 (모든 환자 공통)

• 특징적인 TN 증상 확인 (초단시간 발작성 극심 통증, trigger zone 존재)
• MRI 필수 → 뇌종양, 다발성경화증, 혈관기형 등 이차성 원인 배제

2. TN 분류 (MRI 결과에 따라)

MRI 소견TN 유형

종양, MS 병변, 혈관기형 등	이차성 TN (Secondary)
신경혈관 압박 + 신경 형태 변화	고전적 TN (Classical)
압박 없음	특발성 TN (Idiopathic)

3. 치료 단계

① 이차성 TN

• 가능하다면 원인 질환 치료 (종양 제거, MS 치료 등)
• 원인 치료 불가능하면 일반 TN 치료와 동일하게 진행

② 고전적 TN & 특발성 TN

1차 약물 치료 (First-line)

• Carbamazepine 또는 Oxcarbazepine (최우선 추천)

2차 약물 치료 (Second-line)

• Lamotrigine, Baclofen, Pregabalin, Gabapentin, Phenytoin 등 추가 또는 변경

급성 악화 시

• Phenytoin (정맥 또는 경구)

---

약물 치료 실패 기준

• 서로 다른 약물 최소 2가지를 충분한 용량·기간 투여했음에도
• 통증 조절이 안 되거나, 부작용으로 견디지 못하는 경우

↓ 수술적 치료 고려

4. 수술적 치료

상황추천 치료

신경혈관 압박이 명확하고, 환자 상태 양호	미세혈관 감압술 (Microvascular Decompression, MVD) ← 가장 효과적·지속적
MVD 불가능하거나 실패한 경우	경피적 삼차신경절 시술 • Rhizotomy (신경절 절제) • Thermocoagulation (고주파 열응고) • Balloon compression (풍선 압박) • Gamma Knife 방사선 수술

대안 약물 (증거수준 낮음)

• Botulinum toxin A (보톡스) 주사

삼차신경과 두통 관계

저자들은 유럽 두통연맹 학교(EHF-SAS) 소속 연구자들로,

삼차신경(Trigeminal nerve, CN V)이

대부분의 두통과 안면 통증 병태생리에 핵심 역할을 한다는 점을 강조하며,

해부학·생리학·임상적 의미를 체계적으로 설명합니다.

주요 내용 요약

• 서론: ICHD-3 기준으로 300여 가지 두통·안면통 중 많은 것이 삼차신경과 관련되어 있음.
• 두개내 통증 감수 구조(경막, 혈관 등)는 주로 삼차신경으로 지배되며, 통증이 얼굴·두피로 referred pain(연관통)으로 느껴짐.
• Trigeminovascular system (삼차혈관계): 뇌혈관·경막을 지배하는 삼차신경 섬유. 편두통 발작 시 C- 및 Aδ-섬유 활성화가 핵심. TG(삼차신경절)는 BBB가 없어 약물 표적(트립탄, CGRP 항체 등)으로 중요.

이 논문은
"Migraine and the trigeminovascular system—40 years and counting"
(편두통과 삼차혈관계 — 40년의 기록)이라는 제목의
2019년 Lancet Neurology 리뷰 논문입니다. (PMC7164539, Ashina M et al.)

1979년 Moskowitz 등이 The Lancet에 제시한 trigeminovascular hypothesis(삼차혈관 가설)을 40주년 기념으로 정리한 Personal View입니다. 삼차신경(Trigeminal nerve)과 그 혈관 지배(혈관 주위 신경섬유)가 편두통 통증의 핵심 경로라는 점을 역사적·해부학적·생리학적·치료적 관점에서 종합적으로 다룹니다. CGRP 표적 치료제(항체, gepants) 개발의 이론적 기반을 명확히 보여주는 중요한 리뷰예요.


주요 내용 요약 

• 배경: 20세기 대부분 편두통 원인은 미스터리였으나, 1979년 가설이 삼차신경의 neuropeptide(신경펩티드) 역할을 강조하면서 획기적 변화가 시작됨.
  Substance P → CGRP → PACAP 순으로 연구가 진행됨.
• 해부학 (Anatomy):
  • 삼차신경절(TG)에서 나오는 섬유가 경막(dura mater), 뇌혈관(pial arteries)을 지배.
  • C-섬유(무수초)와 Aδ-섬유(얇은 수초)가 혈관 주위에 밀집.
  • 경추(C1-C2) 신경도 일부 관여 → 편측 두통 설명.
  • TG → spinal trigeminal nucleus (SpV, 특히 caudalis) → thalamus → cortex로 투사.
• 생리학적 기전:
  • Peripheral & Central Sensitization: 말초(경막 nociceptor) 감작 → 중추(SpV, thalamus) 감작 → throbbing pain, allodynia(촉각통), photophobia 등.
  • Cortical Spreading Depression (CSD, aura): 뇌피질 파동이 경막 trigeminovascular axon을 활성화 → headache 유발.
  • Neuropeptides: CGRP(가장 중요, 강력 혈관확장), Substance P, PACAP. 공격 시 방출 증가.
• 치료 연관:
  • Triptans/Ergots: prejunctional inhibition → neuropeptide release 차단.
  • Anti-CGRP mAb (erenumab, fremanezumab 등) & gepants: CGRP 차단.
  • OnabotulinumtoxinA: C-섬유 억제.
  • Ditans (lasmiditan): 5-HT1F agonist.
• Table 1: 1979~2019 주요 발견 타임라인 (가설 제안 → CGRP 유발 실험 → 치료제 개발).
• Table 2: 주요 약물의 작용 기전 및 표적.

결론: trigeminovascular system은 편두통의 final common pathway. BBB 외부 표적( TG, meninges)이 많아 항체·gepants 같은 대분자 약물이 효과적. 앞으로 40년은 더 정밀한 기전(이온채널, 염증 등) 연구와 새로운 치료로 이어질 전망.

그림 설명 (Figure) 논문에 하나의 주요 Figure가 있습니다. (Schematic overview of the trigeminovascular system)

• 전체 구조:
  • Yellow: 경막(dural) 및 pial 혈관에서 오는 afferent (삼차신경 입력).
  • Orange: 경추 dorsal root ganglion 입력.
  • Green: SpV (spinal trigeminal nucleus)에서 나가는 projection.
  • Blue: Thalamus → 다양한 cortex (somatosensory S1/S2, insular, auditory, visual 등)로 가는 thalamo-cortical projection.
  • Peach: efferent (부교감 등) → 경막 혈관.
• 주요 라벨: SpV, PAG, SSN (superior salivatory nucleus), thalamus nuclei (VPM, Pul 등), cortex 영역 (Au, V1/V2, Ins 등).

→ 편두통 증상(통증 + 광음공포 + 구역 + 인지 변화 등)이 왜 동시에 나타나는지를 한눈에 보여줍니다. 뇌( cortex/CSD) ↔ 경막( trigeminovascular) 양방향 상호작용을 강조.

• 삼차신경절(TG, Trigeminal Ganglion): Meckel’s cave에 위치. pseudo-unipolar neuron이 있으며, CGRP 등 신경펩티드 저장. 위성아교세포(SGC)와 상호작용하며 통증 만성화에 관여.
• 삼차신경의 3대 분지:
  • V1 (안신경, Ophthalmic): 눈·이마·코 위쪽, 전두부 두피. 경막·뇌혈관 주요 지배 → 대부분 두통이 V1 영역으로 느껴짐.
  • V2 (상악신경, Maxillary): 뺨·코·윗입술·윗니.
  • V3 (하악신경, Mandibular): 아랫입술·턱·아랫니 + 씹는 근육 운동 지배.
• Trigeminocervical complex (TCC): TG에서 중추로 투사되는 2차 뉴런. 경추(C1-C2)와 연결되어 occipital nerve와 convergence → 후두부 통증도 삼차영역으로 느껴짐.
• 주요 두통과의 연관:
  • 긴장형 두통(TTH): 근막 통증 → 중심 감작(central sensitization).
  • 편두통(Migraine): CGRP 경로 활성화, TG가 주요 표적.
  • 군발두통(CH) 등 TACs: 자율신경 증상 + 삼차 활성화.
  • 삼차신경통(TN): 혈관 압박 등으로 인한 신경병증성 통증.
• 치료: 급성·예방 약물(CGRP 표적 치료제, 트립탄, 보톡스 등), 신경자극(VNS, ONS), 신경차단 등. TG가 많은 치료의 공통 표적.

그림 설명 (Figure)

논문에 주요 그림 2개가 있습니다.

Fig. 1: Schematic of the Trigeminal System (삼차신경계 모식도)

• (a): 삼차신경 nociceptive afferent가 trigeminal nucleus caudalis(TNC)에 체성배열되는 모습 (onion-skin pattern). 입술·입 주변은 가장 rostral(위쪽), 귀·이마는 caudal(아래쪽).
• (b): 얼굴 피부 지배 영역과 V1(파란), V2(녹색), V3(빨강) 3대 분지. PSN, MN, PA, PI, PC 등 brainstem nucleus 표시. → 두통 통증이 왜 특정 얼굴 영역으로 국한되어 느껴지는지 시각적으로 보여줍니다.

Fig. 2: Trigeminal Ganglion (TG) 해부

• 왼쪽: 쥐 해부 사진 – Meckel’s cave에 있는 TG 두 개.
• 오른쪽: TG와 3대 분지.
• 삽입: H&E 염색 – TG 내 neuron 클러스터가 V1/V2/V3 영역별로 somatotopically 조직화되어 있음. → TG가 ‘중앙 허브’라는 점을 실물·조직학적으로 증명.

결론 (논문에서)

삼차신경은 두통의 공통 분모이며, TG는 BBB가 없어 약물 접근이 용이한 핵심 표적. 중추 기전과 결합해야 완전한 이해가 가능하다고 강조

https://pmc.ncbi.nlm.nih.gov/articles/PMC7164539/

Migraine and the trigeminovascular system—40 years and counting - PMC

Lancet Neurol

. Author manuscript; available in PMC: 2020 Apr 17.

Published in final edited form as: Lancet Neurol. 2019 May 31;18(8):795–804. doi: 10.1016/S1474-4422(19)30185-1

Migraine and the trigeminovascular system—40 years and counting

Messoud Ashina 1, Jakob Møller Hansen 1, Thien Phu Do 1, Agustin Melo-Carrillo 1, Rami Burstein 1, Michael A Moskowitz 1

• Author information
• Article notes
• Copyright and License information

PMCID: PMC7164539  NIHMSID: NIHMS1579515  PMID: 31160203

The publisher's version of this article is available at Lancet Neurol

Abstract

The underlying causes of migraine headache remained enigmatic for most of the 20th century. In 1979, The Lancet published a novel hypothesis proposing an integral role for the neuropeptide-containing trigeminal nerve. This hypothesis led to a transformation in the migraine field and understanding of key concepts surrounding migraine, including the role of neuropeptides and their release from meningeal trigeminal nerve endings in the mechanism of migraine, blockade of neuropeptide release by anti-migraine drugs, and activation and sensitisation of trigeminal afferents by meningeal inflammatory stimuli and upstream role of intense brain activity. The study of neuropeptides provided the first evidence that antisera directed against calcitonin gene-related peptide (CGRP) and substance P could neutralise their actions. Successful therapeutic strategies using humanised monoclonal antibodies directed against CGRP and its receptor followed from these findings. Nowadays, 40 years after the initial proposal, the trigeminovascular system is widely accepted as having a fundamental role in this highly complex neurological disorder and provides a road map for future migraine therapies.

초록 (Abstract)

20세기 대부분 동안

편두통 두통의 근본 원인은 수수께끼로 남아 있었다.

1979년 《란셋》에 발표된 새로운 가설은

신경펩티드를 함유한 삼차신경의 핵심 역할을 제안했다.

이 가설은

편두통 연구 분야를 혁신적으로 변화시켰으며,

다음과 같은 주요 개념을 확립하는 데 기여했다:

경막 삼차신경 말단에서 신경펩티드가 방출되는 기전,

편두통 치료제가 신경펩티드 방출을 차단하는 작용,

경막 염증 자극에 의한 삼차 구심성 신경의 활성화 및 감작,

그리고 강렬한 뇌 활동의 상류 역할 등이다.

신경펩티드 연구를 통해

칼시토닌 유전자 관련 펩티드(CGRP)와 substance P에 대한 항혈청이

이들의 작용을 중화할 수 있다는 최초의 증거가 나왔다.

이후 CGRP와 그 수용체를 표적으로 하는 인간화 단클론항체를 이용한

성공적인 치료 전략이 개발되었다.

가설이 처음 제안된 지 40년이 지난 지금,

삼차혈관계는 이 매우 복잡한 신경학적 장애에서 근본적인 역할을 하는 것으로 널리 받아들여지고 있으며,

미래 편두통 치료의 로드맵을 제공하고 있다.

Introduction

Migraine is a highly preval‎ent and complex disorder characterised by an episodic, severe, often unilateral throbbing or pulsating headache associated with nausea, photophobia, phonophobia, and sometimes auras.1 Headaches are often the most troubling feature and the causes and treatments have been extensively researched.

In 1979, Moskowitz and colleagues2 introduced the trigeminovascular hypothesis of migraine in The Lancet, calling attention to a key role for the trigeminal nerve and its vasoactive neuropeptide-containing axonal projections to the meninges and its blood vessels. The model underscored the potential importance of released neuropeptides and their downstream effects after trigeminal activation. The trigeminal innervation became framed as a final common pathway for upstream headache initiation and a fundamental template for new therapeutic directions.3 Crucial to the hypothesis was emerging knowledge about the importance of vasoactive neuropeptide mediator substance P followed later by two even more potent vasoactive peptides, calcitonin gene-related peptide (CGRP; now a proven therapeutic target) and pituitary adenylate cyclase-activating polypeptide (PACAP).

The hypothesis was prescient because it predated both the 1981 discovery of the sensory innervation to the circle of Willis, and the identification of neuropeptide mediators within the trigeminovascular system (a term used from 1983 to describe the trigeminal–meningeal–CNS relationship).4,5 Over the ensuing decades, experimental studies provided crucial insights into the neurophysiology of migraine-related pain with therapeutic implications (eg, allodynia and peripheral and central sensitisation), coherent central mechanisms of migraine-related pain processing, and promising efforts using neuroimaging to discern the relationship between blood vessel function and migraine. These subsequent findings provided fundamental support to the 1979 trigeminal nerve hypothesis and its contributions to the intellectual underpinnings and subsequent developments regarding migraine theory and therapeutics 40 years later.

In this Personal View, we review the most notable concepts and advances that have emerged from the identification of the role of the trigeminovascular system in migraine with an emphasis on future implications and for treatment of this disorder. These include a brief review of historical developments, as well as other major developments in anatomy, neurophysiology, pharmacology, neurochemistry, human pathophysiology, and drug development, all identified using neuroimaging.

서론 (Introduction)

편두통은 매우 흔하고 복잡한 장애로,

주기적으로 발생하는 심한 편측성 맥동성 또는 박동성 두통을 특징으로 하며,

메스꺼움, 광공포증, 음공포증,

때로는 전조(aura)를 동반한다.¹

두통은 종종 가장 고통스러운 증상이며,

그 원인과 치료법은 광범위하게 연구되어 왔다.

1979년 Moskowitz와 동료들²은 《

란셋》에 편두통의 삼차혈관 가설(trigeminovascular hypothesis)을 발표하면서,

삼차신경과 그 혈관활성 신경펩티드를 함유한 축삭이 경막과 혈관으로 투사되는 역할을 강조했다.

이 모델은 삼차신경 활성화 후 방출되는 신경펩티드와 그 하류 효과의 중요성을 부각시켰다. 삼차신경 지배는 상류 두통 유발의 최종 공통 경로(final common pathway)로, 새로운 치료 방향의 기본 틀로 자리 잡았다.³

이 가설의 핵심은 당시 새롭게 부각되던 혈관활성 신경펩티드 물질인 substance P, 그리고 이후 더 강력한 두 가지 펩티드 — 칼시토닌 유전자 관련 펩티드(CGRP, 현재 입증된 치료 표적)와 뇌하수체 아데닐산 cyclase 활성화 폴리펩티드(PACAP) — 에 대한 지식이었다.

이 가설은 선견지명적이었다. 1981년 Willis 동맥환의 감각 신경 지배가 발견되기 전, 그리고 삼차혈관계(trigeminovascular system)라는 용어가 1983년에 처음 사용되기 전에 이미 제안되었기 때문이다.⁴⁵ 그 후 수십 년 동안 실험 연구들은 편두통 관련 통증의 신경생리학(예: 이질통, 말초 및 중추 감작), 편두통 통증 처리의 일관된 중추 기전, 혈관 기능과 편두통의 관계를 밝히는 신경영상 연구 등에 중요한 통찰을 제공했다. 이러한 후속 발견들은 1979년 삼차신경 가설을 강력하게 뒷받침했으며, 40년 후 편두통 이론과 치료 개발의 지적 토대를 마련하는 데 크게 기여했다.

본 Personal View에서는 삼차혈관계가 편두통에서 수행하는 역할에서 나온 가장 주목할 만한 개념과 발전을 검토한다. 특히 미래 치료 방향에 중점을 두고, 역사적 발전, 해부학, 신경생리학, 약리학, 신경화학, 인간 병태생리학, 신경영상학을 이용한 약물 개발 등 주요 발전을 다룬다.

Early findings and further development of the trigeminovascular modelAnatomy

The term trigeminovascular was introduced to encompass the immunohistochemical and neurochemical findings associated with the trigeminal pathway to pial arteries in multiple species, including humans.5,6 Further studies confirmed this new pathway and the well-known trigeminal innervation of the dura mater (table 1).4,7 In cats, upper cervical dorsal root ganglia contribute additional meningeal innervation and together these path ways provide an anatomical substrate for hemicranial pain.31 Within the meninges, the largest density of small diameter unmyelinated C-fibres and thinly myelinated Aδ-fibre axons (of trigeminal origin) are found in blood vessels. Experimental studies in humans showed that electrical or mechanical stimulation of large meningeal blood vessels are associated with headache, whereas areas remote from vessels often are not.32 In mice, dural axons of nociceptors have been observed issuing pial branches that cross the arachnoid space and suture branches that reach the periosteum and possibly some pericranial muscles. These axons establish a direct route of communication between extracranial and intracranial events that can activate nociceptors on both sides of the calvarial bones.33

삼차혈관 모델의 초기 발견과 추가 발전

(Early findings and further development of the trigeminovascular model) 해부학 (Anatomy)

‘삼차혈관계(trigeminovascular)’라는 용어는 여러 동물종(인간 포함)에서 삼차신경이 연질막(pial) 동맥으로 가는 경로와 관련된 면역조직화학적·신경화학적 발견을 포괄하기 위해 도입되었다.⁵⁶ 이후 연구에서 이 새로운 경로와 잘 알려진 경막(dura mater)의 삼차신경 지배가 확인되었다(표 1).⁴⁷

고양이 실험에서는 상부 경추 dorsal root ganglia가 경막 지배에 추가로 기여하는 것으로 밝혀졌으며, 이 두 경로가 함께 편측 두통(hemicranial pain)의 해부학적 기저를 제공한다.³¹ 경막 내에서는 삼차신경 기원의 작은 직경의 무수초 C-섬유와 얇은 수초 Aδ-섬유가 혈관 주위에 가장 밀집되어 있다.

인간 실험 연구에서는 큰 경막 혈관을 전기적·기계적으로 자극할 때 두통이 유발되지만, 혈관에서 떨어진 부위는 그렇지 않다는 것이 확인되었다.³² 쥐 실험에서는 경막 nociceptor의 축삭이 연질막 가지를 내고 지주막 공간을 가로질러 봉합(suture) 가지를 통해 골막(periosteum)과 일부 두개 외 근육까지 도달하는 것이 관찰되었다. 이 축삭들은 두개골 양쪽의 nociceptor를 활성화할 수 있는 두개 내·외 사건 간 직접적인 소통 경로를 만든다.³³

Table 1:

Major, original discoveries—the trigeminovascular system

YearBrief description

The trigeminovascular hypothesis2	1979	Proposed a pathophysiological link between migraine and the trigeminal innervation of the meninges, and a potential role for the undiscovered vasoactive neuropeptide transmitters as therapeutic targets
Perivascular meningeal axons project from the trigeminal ganglia4	1981	Sensory innervation to the circle of Willis shown by axonal tracing techniques. Labelled cell bodies found in the ipsilateral trigeminal ganglia after horseradish peroxidase was applied to the feline middle cerebral artery
The neuropeptide-containing trigeminovascular system is named5	1983	The trigeminovascular system is named and its first neuropeptide identified. The trigeminovascular system is now considered a functional unit on the basis of anatomy, physiology, and pathology of meningeal afferents and their central connections
Neuropeptide within the trigeminovasulcar system is released from meninges8	1983	In vitro release of a vasoactive neuropeptide substance P from its trigeminovascular afferents by calcium-dependent mechanisms, suggesting a role as a neuromediator within the meninges
CGRP is released from trigeminal ganglion cells9	1984	Immunoreactive CGRP is spontaneously released by cultured trigeminal ganglion cells in a calcium-dependent manner
CGRP and substance P coexist in the trigeminal ganglion and nerve fibres around cerebral blood vessels10	1985	The presence of CGRP in cerebrovascular trigeminal innervation provides further versatility and complexity for this sensory afferent system putatively involved in the transmission of intracranial pain
Ergot alkaloids inhibit neuropeptide release11	1988	Pharmacological evidence that ergot alkaloids inhibit neuropeptide release within meninges following electrical trigeminal stimulation. A prejunctional inhibitory receptor-driven mechanism was proposed for ergot alkaloids
CGRP released upon activation of the trigeminal system in humans12	1988	In vivo human data showing that plasma CGRP levels are increased upon thermal coagulation of the trigeminal ganglion
Proof of concept for antibody targeting of neuropeptides13	1989	Antisera directed against CGRP and substance P blocked the peripheral actions of released peptides in neurogenic inflammation
Sumatriptan inhibits neuropeptide release14	1990	Pharmacological evidence that sumatriptan inhibits neuropeptide release within meninges following electrical trigeminal stimulation. A prejunctional inhibitory receptor-driven mechanism was proposed for sumatriptan
Migraine drugs decrease CGRP release during trigeminal stimulation15	1991	Dihydroergotamine and sumatriptan decreased CGRP blood levels during electrical trigeminal ganglia stimulation
Migraine drugs attenuate CGRP levels during attacks16	1993	Elevated CGRP blood levels during spontaneous migraine attacks are attenuated by dihydroergotamine and sumatriptan
Brain stem activation in spontaneous human migraine attacks17	1995	During spontaneous migraine attacks, blood flow increased in cingulate, auditory, and visual association cortices (cerebral hemispheres) and in the brainstem. Increased blood flow persisted after headaches, and phonophobia and photophobia were completely relieved by sumatriptan. The findings suggest that migraine is associated with an imbalance in activity between brain stem nuclei and vascular control
Neuronal substrate of throbbing is revealed18	1996	Dural stimulation converts peripheral trigeminovascular neurons from mechanically insensitive to mechanically hypersensitive, which explains throbbing and intensification of headache by coughing or bending over
Neuronal substrate of scalp tenderness and allodynia is revealed19	1998	Dural stimulation produces long-lasting sensitisation of central trigeminovascular neurons in the spinal trigeminal nucleus
The 5-HT1F receptor modulates activity of the trigeminal system20	1999	LY 344864, a selective 5-HT1F receptor agonist attenuates capsaicin provoked early-immediate gene response (c-fos expression‎) in the spinal trigeminal nucleus. The fact that a 5-HT1F agonist modulates activity within the trigeminovascular system suggests its potential as a drug target
Cephalic allodynia is unique to migraine21	2000	Cephalic allodynia is unique to headaches and involves irritation of pain fibres in the dura. This symptom can take years to appear in patients.
A link between migraine aura and headache is identified22	2002	Cortical spreading depression activates trigeminovascular afferents and promotes a series of cortical meningeal and brainstem events consistent with evoking headache
CGRP triggers migraine in humans23	2002	Intravenous infusion of CGRP triggers migraine attacks without aura in patients with migraine
Proof of concept for CGRP-targeted treatment24	2004	Olcegepant, a small molecule CGRP receptor antagonist, shows clinical efficacy in an acute clinical trial with 34 migraine patients
PACAP triggers migraine in humans25	2009	Intravenous infusion of PACAP dilates extracerebral arteries and triggers migraine attacks without aura in patients
The link between migraine aura and headache is further explored26	2010	Cortical spreading depression leads to long-lasting activation of nociceptors that innervate the meninges
Evidence for a meningeal contribution to migraine pain27	2011	CGRP-induced migraine headache is associated with ipsilateral dilation of extracerebral and intracerebral arteries. Constrictions of the extracerebral middle meningeal artery (but not intracerebral arterial constriction) parallels a reduction in headache intensity
Simple arterial dilatation is not the cause of migraine pain28	2013	Spontaneous migraine attacks were not accompanied by extracerebral arterial dilatation, or substantial intracerebral dilatation overall. In the few vessels showing enlarged diameters, dilatation persisted even after relief from headache by sumatriptan. These results shifted the focus to peripheral and central pain pathways rather than simple arterial dilatation
Anti-CGRP monoclonal antibodies are effective in the prevention of episodic migraine29	2014	This trial showed clinical efficacy and safety, suggesting that anti-CGRP monoclonal antibodies might be a viable therapy for prevention of episodic migraine
Meningeal contribution to migraine pain is further explored30	2019	Cilosazol-induced migraine is associated with mild dilation of the middle meningeal artery on the headache side. Hence, dilation of this artery could serve as a surrogate marker for activation of dural perivascular nociceptors, indicating a meningeal site of migraine headache

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5-HT=hydroxytryptamine (serotonin). CGRP=calcitonin gene-related peptide. PACAP=pituitary adenylate cyclase-activating polypeptide

In cats and rodents, trigeminal ganglion neurons projecting to the meninges send central axons that reach trigeminovascular neurons in the spinal trigeminal nucleus, where they converge on neurons that receive additional input from the periorbital skin and pericranial muscles (figure).10,34,35 Axonal projections of 2nd-order trigeminovascular neurons convey pain signals to multiple nuclei in the brainstem, hypothalamus, basal ganglia, and thalamus.37 These projections might mediate autonomic (nausea, vomiting, yawning, lacrimation, urination), affective (anxiety, irritability), and hypothalamic-regulated functions related to keeping homoeostasis (loss of appetite, fatigue).38 Relay trigeminovascular thalamic neurons projecting widely (eg, to the somatosensory, insular, auditory, visual, and olfactory cortices) contribute to the specific nature of migraine pain and the many cortically mediated symptoms in migraine. These include transient symptoms of allodynia, phonophobia, photophobia, and osmophobia.39

Figure: Schematic overview of the trigeminovascular system.

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Adapted from Burstein et al.36 Thalamic trigeminovascular neurons project to a wide array of cortical areas that mediate symptoms associated with migraine, such as transient amnesia and cognitive decline, phonophobia, photophobia, and expressive aphasia. Inputs to SpV arise from meningeal dural blood vessels and pial blood vessels (not shown). Green: projections from SpV. Blue: thalamo-cortical projections. Yellow: afferent projections from meningeal blood vessels. Orange: afferent projections from cervical dorsal root ganglions.Peach: efferent projections to meningeal blood vessels. Au=Auditory cortex. ECT= ectorhinal cortex. Ins=insular cortex. LP=lateral posterior thalamic nucleus. M1=primary motor cortex. M2=secondary motor cortex. PAG=periaqueductal gray. PB=parabrachial nucleus. Po=posterior. PtA=parietal association cortex. Pul=pulvinar. RS=retrosplenial cortex. S1=primary somatosensory cortex. S2=secondary somatosensory cortex. SpV=spinal trigeminal nucleus. SSN=superior salivatory nucleus. V1=primary visual cortex. V2=secondary visual cortex. VPM=ventral posteromedial

Because pathways conveying migraine headaches involve both peripheral and CNS components, deciphering this association is complex. Under circumstances such as cortical-spreading depress ion, intense neuroglial activity in grey matter activates signaling cascades that could, in turn, discharge adjacent meningeal trigeminovascular axons. The brain, via spinal trigeminal nucleus inputs and rostral structures, processes and integrates transmitted information to generate migraine headache. Hence, the same organ that processes incoming signals relevant to the generation of headache also depolarises trigeminovascular afferents.

Neurophysiological mechanisms

Migraine aura is the clinical manifestation of cortical spreading depression (CSD).3,40 The aura is characterised by a propagating wave of cellular excitability that is followed by a long period of hyperpolarisation and a consequent headache that is thought to be initiated at least partly by introduction of inflammatory molecules and CGRP to the dura.41

In rodents, CSD initiates delayed and immediate activation of trigeminovascular neurons in the trigeminal ganglion and spinal trigeminal nucleus. Such activation patterns appear similar to the delayed and immediate onset of headache after aura in patients.26,42 These findings support the view that the initiation of headache depends on activation of meningeal nociceptors at the origin of the trigeminovascular pathway. Neuropeptide-induced dural neurogenic inflammation and mast cell degranulation might play a role in the activation or sensitisation of dural nociceptors.43 When activated in the altered molecular environment, peripheral trigeminovascular neurons become sensitised, and in turn, sensitize second and third order trigeminovascular neurons in the spinal trigeminal nucleus and the thalamus.38,44 Intensification of headache when bending over is the manifestation of peripheral sensitisation, whereas cephalic and extracephalic allodynia is the manifestation of sensitisation of trigeminovascular neurons in the spinal trigeminal nucleus and the thalamus.21

Triptans are a class of selective serotonin 5-hydroxytryptamine (5-HT1B) receptor agonists used to treat acute migraine. They disrupt communications between peripheral and central trigeminovascular neurons and are more effective in aborting migraine when given early—before the development of central sensitisation—providing further support to the notion that meningeal nociceptors drive the initial phase of the headache.45 Sumatriptan binds to 5-HT1B receptors in the brain that are associated with known CNS-related adverse events such as dizziness and somnolence, but it is unclear if this CNS binding is relevant for sumatriptan’s therapeutic effect in migraine.46 Further support for disrupted communication is found in studies showing that two peripherally acting drugs, onabotulinumtoxinA and anti-CGRP monoclonal anti bodies (mAbs), effectively prevent migraine in patients by inhibiting the activation and sensitisation of different classes of peripheral meningeal nociceptors. OntabotulinumtoxinA inhibits C fibres, but not Aδ-type meningeal nociceptors.47 Anti-CGRP monoclonal antibodies inhibit thinly myelinated (Aδ) but not unmyelinated (C) meningeal nociceptors.48

Neuropeptides

Three powerful vasodilating peptides are found within trigeminal afferents innervating the meninges (substance P, CGRP, and PACAP). The tachykinin substance P, discovered in 1931, is widely distributed in both the PNS and CNS, including the cranial vasculature, ganglia, and trigeminal sensory afferents.49 Preclinical experiments showed that substance P is widely implicated in pain transmission.50 Substance P resides in small diameter ganglion cells and co-exists to a great extent with CGRP in small unmyelinated fibres.10 Unilateral lesions of the trigeminal ganglia (or sectioning of its meningeal branches) decrease substance P in ipsilateral large cephalic blood vessels.5,51 These findings provided evidence that substance P is released into surrounding tissues from perivascular axons derived from the trigeminal nerve.43 However, as only a minority of trigeminal ganglion cells projecting to the meninges contain substance P, the presence of additional sensory neuromediators within the trigeminovascular system was suspected.7

CGRP, discovered in 1982, was the second neuropeptide to be identified in the trigeminovascular system, with effects in vascular tissues similar to those observed with substance P. CGRP is one of the most potent vasodilators of intracranial blood vessels, elicits a greater vasodilation than substance P, and its depletion leads to a decrease in the diameter of the ipsilateral arterial lumen.10,16 CGRP is found in perivascular trigeminal sensory afferents, and fibres containing CGRP are especially abundant in the walls of the cerebral arteries of the circle of Willis.52 Similar to substance P, CGRP is released by stimulation of meningeal afferents, and calcium - dependent release of CGRP in cultured trigeminal ganglion cells supported its role as an extracellular modulator.9,53 The findings are consistent with in vivo data from a study of nine patients with trigeminal neuralgia and five cats, which showed that plasma CGRP concentrations are increased during thermocoagualation of the trigeminal ganglion in humans and during electrical stimulation of the trigeminal gang lion in cats.12 Electrical stimulation of the trigeminal ganglion releases neurokinin A, substance P, and CGRP simultaneously, suggesting that substance P is not alone in modulating trigeminal pathways.54 Additional data are required to clarify this point; however, the importance of CGRP in migraine and to the human trigeminovascular system was shown by the success of strategies to block the effect of CGRP, whereas a substance P receptor blocker was not effective in clinical trials. Despite the negative outcome, the latter trials were the first to test a bench-to-bedside approach to therapy, did not depend upon a vascular smooth muscle mechanism, and focused on products contained within and released from the trigeminovascular system. The progression of targeting one peptide to the next was then systematically approached by the pharmaceutical industry. Their differing success underscores the need to better understand why selectively blocking one neuromediator and not another effectively treats migraine or why targeting CGRP appears more useful for mitigating headache than it does other visceral or somatic pains.55

PACAP, discovered in 1989, exists in two bioactive forms.56 PACAP is found in trigeminal nerve fibres around cerebral blood vessels.56 Furthermore, it can be found in the trigeminal ganglia, the sphenopalatine, and the trigeminal nucleus caudalis.56 Similar to CGRP, PACAP plasma concentrations increase during electrical stimulation of the trigeminal ganglion and superior sagittal sinus.57,58 However, PACAP concentrations decrease in both plasma and the trigeminal ganglion during dural application of inflammatory substances, perhaps reflecting responses to the nature of different stimuli.56 The clinical importance of PACAP is still primarily hypothesis driven as results of drug trials targeting PACAP and its receptor are pending.

Receptor subtypes

The 5-HT1B/1D/1F receptor subtypes are widespread in the trigeminovascular system. In 1988, a clinical trial59 reported a possible benefit from a novel 5-HT1-ike receptor agonist GR43175 (nowadays known as sumatriptan) for treatment of acute migraine. The same year, pharmacological experiments revealed that ergot alkaloids block neuropeptide release in the meninges following electrical trigeminal stimulation, a finding later replicated for sumatriptan.11,15 Both triptans and ergot alkaloids reduced elevated CGRP plasma concentrations during electrical trigeminal stimulation in rats.15 Taken together, these experimental studies provided the first pharmacological evidence for a prejunctional site of drug activity that coupled serotonin receptor subtypes to inhibition of neuropeptide release, now considered the most coherent therapeutic mechanism for ergots and triptans. These findings directed research away from vascular smooth muscle and towards targeting released trigeminal neuropeptides and their receptors.60

Preclinical discoveries showed that the 5-HT1B/1D subtypes reduce substance P and CGRP release in the trigeminal ganglion and trigeminal nucleus. Furthermore, using other experimental paradigms, 5-HT1 agonists also induce vasoconstriction in intracranial arteries.61 The 5-HT1D receptor subtype plays a possible role in inhibiting CGRP release from trigeminal neurons.62 The 5-HT1F receptor subtype also resides in the trigeminal gang-lion, trigeminal nucleus caudalis, and cerebral vessels; however, unlike the other subtypes, the 5-HT1F receptor subtype does not induce vasoconstriction.63

Substance P binds to the G-protein coupled receptors neurokinin-1 (NK), NK2, and NK3, with highest affinity for NK1 located in the dorsal horn of the spinal cord, the locus coeruleus, and the raphe nucleus.49 Following substance P release, NK1 receptors are activated in the endothelium and cause vasodilation, mast cell degranulation, and plasma protein leakage. NK1 receptor antagonists inhibit substance P-induced vasodilation of pial arteries in vivo.49 However, changes in vascular tone evoked by elec trical stimulation of the trigeminal ganglion are unaffected by NK1 receptor antagonists.64 Hence, receptors and neurotransmitters other than NK1 and substance P are pivotal in evoking neurogenic vasodilation.

The CGRP receptor complex is found in the trigeminal ganglion in all investigated species.65 Although CGRP is expressed in C-fibres, receptor components are found in the thicker Aδ-ibres. Furthermore, receptor components are found in neurons of the trigeminal ganglion. Stimulation of the CGRP receptor increases intracellular cyclic adenosine monophosphate (cAMP) by activating adenylate cyclase.66 CGRP is also a ligand for the amylin receptor.66 The potential role of the amylin receptor in migraine is unknown.

PACAP binds to several G-protein coupled receptors including pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1), vasoactive intestinal polypeptide receptor 1 (VPAC1), and VPAC2, which results in increased intracellular cAMP concentra tions.56 The mRNA of these receptors is found in several structures including the trigeminal ganglia and otic ganglia, and all three receptors are found in cerebral and cranial blood vessels. The VPAC1 and VPAC2 receptors mediate vasodilation and mast cell degranulation, whereas the PAC1 receptor is involved in multiple biological processes.56 Notably, the released contents from mast cell degranulation activate C-fibres innervating the dura mater.67 Furthermore, a PAC1 receptor antagonist attenuates nociception in models of inflammatory and chronic pain, emphasising its role in nociception.68,69 Central activation of the PAC1 receptor appears to mediate the effects of PACAP on central trigeminovascular neurons.70

Neurogenic inflammation

Plasma extravasation and vasodilation are both important components of the neurogenic inflammatory response, and substantial additional evidence suggests a role for other signaling markers of inflammation in migraine.71 Neurogenic inflammation develops because of release of sensory neuropeptides such as substance P and CGRP from innervating fibres, and this release of neuropeptides might also occur in extracranial pain sensitive structures.71,72 Studies focused on the dura mater, a structure that contains vessels outside of the blood–brain barrier, and perivascular nerves and mast cells, showed that chemical and electrical stimulation induces plasma extravasation in the dura mater but not the brain, which remains protected behind the blood–brain barrier.73 Administration of indometacin, acetylsalicylic acid (aspirin), ergotamine tartrate, dihydroergotamine, or triptans blocked neuro genic extra vasation in the dura mater in animal models, as did substance P receptor antagonists.14,74,75 The same studies implicated prejunctional mechanisms and pep tide release inhibition by ergot alkaloids and triptans. Several substance P receptor antagonists blocked plasma protein extravasation in preclinical models.49 However, human clinical trials were ineffective when testing oral and intravenous administration of a substance P receptor antagonist, which indicated that substance P-induced neurogenic inflammation is not sufficient to explain human migraine headache; nevertheless, it could be a useful biomarker indicative of a meningeal inflammatory response.49

However, the CGRP-induced neurogenic vasodilation component of inflammation could be more clinically relevant than is substance P-induced vasodilation. Although neuropeptide release from sensory fibres is getting increasing attention in neuroimmune modulation, research on tissues suggests that the role of neuropeptide release in pain generation remains to be elucidated. Despite these uncertainties, models of neurogenic inflammation provided the data to support pursuing new therapeutic targets (eg, the 5-HT1F receptor subtype) as well as the therapeutic use of monoclonal antibodies.76 Antisera directed against CGRP and substance P blocked the peripheral actions of these peptides, which was a discovery predating that of the efficacy of therapeutic monoclonal antibodies in migraine by 30 years.13

Clinical imaging evidence for trigeminovascular migraine mechanisms

Results from neuroimaging studies have given novel insights into migraine pathophysiology. Although the aura has been notoriously difficult to study, aura-like episodes with corresponding regional blood flow changes consistent with CSD follow carotid puncture.77 Blood flow studies and fMRI studies during spontaneous and evoked visual auras confirm‎ and extend these aura findings77 and reveal spatial and temporal changes in blood oxygen level-dependent signals characteristic of CSD in preclinical models.78,79

Regarding headache, simple vasodilation does not appear to explain the complex phenotype long considered to be the cause of migraine pain. For example, conflicting results were reported using magnetic resonance angiography of the middle meningeal artery, perhaps because of timing variations from attack onset. Results ranged from no dilatation, to ipsilateral dilatation on the pain side, and to dilatation in the early phase followed by bilateral dilatation.27,30,80 By contrast, spontaneous attacks are accompanied by intracranial but not extracranial arterial dilatation,28 and the magnitude of the dilation is minimal. From these studies, it appears unlikely that middle meningeal artery dilation generates migraine pain. Instead, observed changes in vessel diameter could reflect changes in the chemical milieu of the perivascular space and autonomic pain-related reflexes.22

Neuroimaging studies confirm‎ the involvement of trigemi nal structures in migraine. PET studies show increased blood flow in the pons (a surrogate for activation) both during spontaneous attacks and those induced by glyceryl trinitrate.17,81 Lowered basal spinal trigeminal nucleus activity was shown outside of migraine attacks in patients with migraine compared with controls (healthy volunteers who did not have a history of migraine), and this basal level of activity increased at closer timepoints to an episode of migraine.82 Studies in humans also showed increased hypothalamic activity before spontaneous attacks (one patient monitored for 30 consecutive days) and in the premonitory phase of attacks induced by glyceryl trinitrate.83,84 Furthermore, spontaneous migraine attacks were associated with altered functional coupling between the hypothalamus with the spinal trigeminal nucleus the day before and during onset of the attacks.84

Development of drug targets

Putative mechanisms and targets identified in preclinical experiments require translation and at least partial validation in a human model, because migraine could be a uniquely human experience. However, spontaneous attacks are difficult to identify and investigate, especially at their onset. To overcome this challenge, a human model was developed in which migraine attacks were provoked by administering substances to patients with a history of migraine. Attacks, though painful, are fully reversible, making experimentally induced migraine an acceptable model for studying the complex pathophysiological events that occur during a migraine attack.85

In this human model, CGRP, PACAP, or drugs that target downstream signaling cascades following neuropeptide receptor engagement (presumably in proximity to the trigeminovascular pathways) cause typical migraine headaches after infusion. 60–70% of patients experience attacks after infusion of CGRP or PACAP.85 Higher attack rates (>80%) can be observed following administration of phosphodiesterase 3 and 5 inhibitors, implicating the second messengers cAMP and cyclic guanosine mono phosphate. Amplification of both second messengers could suggest a shared target such as modulation of an ion channel (eg, KATP channels).85,86 These studies further emphasise the role of neuropeptides as crucial mediators of migraine and potential drug targets for mechanism-based migraine treatment (table 2).

Table 2:

Drugs used to treat or prevent migraine with putative sites of action

Year of introduction for clinical useAcute or preventive drugForms of administrationType of drugMechanism of actionPossible sites of action

Ergotamines*	1926	Acute	Intravenous; nasal spray; oral	5-HT1B,1D,1F receptor agonist	Inhibits peptide release	Prejunctional receptors
Triptans	1991	Acute	Nasal spray; oral; sublingual; subcutaneous	5-HT1B,1D/1F receptor agonist	Disrupt communication between peripheral and central trigeminovascular neurons	Prejunctional receptors; presynaptic inhibition at the dorsal horn
OnabotulinumtoxinA	2010	Preventive	Intramuscular; subcutaneous	Cleaves intracellular SNARE proteins	Cleaves SNAP25 and prevents adhesion of synaptic vesicles to the cell surface membrane, resulting in inhibition of neuropeptides or neurotransmitter release, and insertion of new receptors	Unmyelinated C-class trigeminovascular meningeal nociceptors; unmyelinated C-class cervicovascular extracranial nociceptors
Monoclonal antibodies†	2018	Preventive	Subcutaneous; intravenous	CGRP-receptor antagonist	Neutralises circulating neuropeptides (or peptide receptor blockade)	Trigeminal ganglion; meningeal nociceptors
Ditans‡	Not yet introduced	Acute	Oral	5-HT1F receptor agonist	Inhibits peptide release	Central sites and peripheral prejunctional receptors
Gepants§	Not yet introduced	Acute and preventive	Oral	CGRP-receptor antagonist	Peptide receptor blockade	Trigeminal ganglion; meningeal nociceptors; spinal trigeminal nucleus

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5-HT=hydroxytryptamine (serotonin). SNARE=soluble NSF attachment protein receptor. CGRP=calcitonin gene-related peptide. PACAP=pituitary adenylate cyclase-activating peptide.

*

Ergotamines are non-selective for 5-HT and are active at adrenergic and other receptor sites.

†

Anti-PACAP38 monoclonal antibodies are in pre-clinical development and will be administered subcutaneously. Anti-PAC1 receptor antibodies are awaiting public results from phase II trials.

‡

The first ditan (lasmiditan) is expected to be approved by the US Food and Drugs Administration in 2019.

§

The first gepants (rimegepant and ubrogepant) are expected to be approved by the US Food and Drugs Administration in 2019 or 2020.

Since the introduction of the triptans, other drug classes with equivalent clinical efficacy but that do not induce vasoconstriction have been sought for treatment of acute migraine. Candidates include agonists at the 5-HT1F receptor that is expressed on trigeminovascular afferents. One of these agonists, lasmiditan, showed a therapeutic effect similar to sumatriptan in a phase 3 randomised multicenter study with 1856 patients with migraine.87 A high frequency of CNS-related adverse events, such as dizziness and somnolence, suggests that this drug (unlike most triptans) penetrates and possibly targets receptors in the brain. However, these adverse effects are unlikely to hinder a future approval of the drug.

The first drug specifically targeting CGRP was the small molecule CGRP receptor antagonist, olcegepant. Although the drug was never commercialised because it is poorly absorbed via oral administration and had limitations when adminstered intravenously, a proof of concept study with 34 patients with migraine showed that 71% of attacks treated with the highest dose resulted in complete relief of symptoms.24 Nowadays, other gepants (atogepant, rimegepant, and ubrogepant) might be nearing use in clinical practice because phase 3 trials for acute migraine attacks and phase 2 trials for preventive treatment are ongoing. Anti-CGRP mAbs have been approved by both the Food and Drug Administration and European Medical Agency and are highly effective and well tolerated; however, 30–40% of patients do not respond to mAbs.88

The site of action of gepants and mAbs is probably outside of the blood–brain barrier (similar to the ergot alkaloids and triptans) as they do not readily cross it. Possible sites of action include meningeal nociceptors and cells and other targets within the trigeminal ganglion.48,89 Two mAbs against PACAP (ALD1910 [preclinical stage]) and against PAC1 receptor (AMG-301 [phase II trial, NCT03238781]) are being developed and tested.

Conclusion and future research

Fundamental insights and discoveries to understand migraine pathophysiology have led to the emergence of new therapies and targets. However, as in most drug discovery research, the road from bench to bedside has not been straightforward. The time from concept to bedside drug therapy can be more than 30 years, which holds true for therapeutic developments in migraine coming to fruition—2019 will mark the 40-year anniversary of the first publication of the trigeminovascular hypothesis.90

The original trigeminovascular hypothesis successfully anticipated the therapeutic importance of identifying and targeting for therapy neuromediators within a final common pathway transmitting pain signals for headache; offered a more coherent understanding of triptan and ergot action also relevant to the role of released neuropeptides; reinforced the notion that clinically effective drugs do not require blood–brain barrier penetration; provided novel concepts concerning activation and sensitisation of trigeminal afferents by meningeal inflammatory stimuli as well as by intense endogenous brain activity; and emphasised the trigeminal nerve as a target for substances originating within the circulation or released from the brain that trigger headache.

The final common migraine pathway continues as an exciting avenue for discovery and as a vehicle to resolve pressing unanswered questions, such as the exact molecular mechanisms responsible for the initation of migraine attack. Future studies will aim to define the role of candidate mutations or polymorphisms that better inform about the initiating or suppressing mechanisms within the trigeminovascular system that lead to headache. Potential research avenues for clinically useful drugs might be found among ion channels ex pressed on trigeminovascular afferents or in meningeal tissues (eg, transient receptor potential vanilloid family, acid-sensing ion channels, potassium channels). Finally, future studies will investigate other aspects of migraine pathogenesis including the role of inflammation as well as vascular factors—eg, endothelial dysfunction.

Drugs targeting key signaling pathways in the trigeminovascular system will continue to transform clinical practice, thus supporting the development of mechanism-based migraine treatment. The hypothesis published in The Lancet in 1979 changed the research direction and focus at that time and was undoubtedly the first important building block upon which migraine research nowadays is based. With the emergence of new tools and technologies to study pain and neurovascular mechanisms, we anti cipate that the next 40 years will bring keystone discoveries to better understand and treat this enigmatic disorder.

Search strategy and selection criteria.

We identified articles published in English through searches of PubMed, Science Direct, Ovid Medline, Embase, and OVID, with use of the search term “trigeminovascular system”. No publication date restrictions were applied. We also identified papers from the authors’ own files and from references cited in relevant articles. We emphasised original and first to publish research and the references were chosen to reflect the laboratory credited with those original discoveries. Reviews were chosen when space did not permit a more comprehensive treatment of a topic or when limited space did not permit coverage of areas relevant to migraine but not necessarily of immediate importance to developments related to the trigeminovascular system. We generated the final reference list on the basis of articles’ relevance to the topic of this Personal View.

Footnotes

Declaration of interests

MA has received personal fees from Alder BioPharmaceuticals, Allergan, Amgen, Alder, Eli Lilly, Novartis, and Teva. MA also participated in clinical trials as the principal investigator for Alder, Amgen, electroCore, Novartis, and Teva. MA also serves as an associated editor of Cephalalgia, associated editor of the Journal of Headache and Pain, is President-elect of the International Headache Society, and General Secretary of the European Headache Federation. RB has received grant support for his studies on migraine pathophysiology from Teva, Allergan, Dr Reddy, and Trigemina; he also serves as a consultant to Alder Biopharm, Allergan, Amgen, Autonomic Technologies, Avanir, Biohaven, Depomed, Dr Reddy, Electrocore, Johnson and Johnson, Neurolief, Percept, Pernix, Strategic Science and Technologies, Teva, Theranica, and Trigemina. RB and Beth Israel Deaconess Medical Center hold a provisional patent on the use of narrow band green light for the treatment of photophobia in migraine. MAM serves as a consultant for Pear Therapeutics and NeuroTrauma Sciences. JMH, TPD and AM-C declare that they have no competing interests.

References

• 1.GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018; 17: 954–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 2.Moskowitz MA, Reinhard JF, Romero J, Melamed E, Pettibone DJ. Neurotransmitters and the fifth cranial nerve: is there a relation to the headache phase of migraine? Lancet 1979; 2: 883–85. [DOI] [PubMed]\

https://pmc.ncbi.nlm.nih.gov/articles/PMC12604400/

The vessel-to-neuron trigeminovascular hypothesis of migraine pathogenesis – the ‘pro’ argument - PMC

J Headache Pain

. 2025 Nov 10;26(1):248. doi: 10.1186/s10194-025-02130-z

The vessel-to-neuron trigeminovascular hypothesis of migraine pathogenesis – the ‘pro’ argument

Rune Häckert Christensen 1,2,3, Håkan Ashina 1,2, Messoud Ashina 1,2,3,✉

• Author information
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PMCID: PMC12604400  PMID: 41214549

AbstractPurpose

The pathogenesis of migraine remains incompletely understood, with traditional theories oscillating between purely vascular or strictly neuronal concepts. However, emerging evidence points to a more integrated “vessel-to-neuron” mechanism. This debate paper explores the role of intracranial vasculature in initiating migraine pain, offering a unifying concept that reconciles these traditionally divergent views.

Findings

Neurosurgical findings confirm‎ that stimulating or mechanically distending intracranial arteries can elicit migraine-like pain, suggesting that these vessels might serve as substrates for migraine pathogenesis. Activation of the trigeminovascular system and subsequent release of migraine-inducing neuropeptides lead to neurogenic inflammation within the meninges, promoting both vasodilation and the sensitization of meningeal nociceptors. Interestingly, all identified molecular migraine triggers potently dilate the intracranial vasculature, converging on potassium efflux from vascular smooth muscle cells. This efflux likely modifies local chemical gradients, thereby depolarizing trigeminal afferents and driving the cascade of ascending nociceptive signaling. Therapeutic interventions further reinforce the causal role of vascular contributions to migraine pathogenesis. Blocking vasodilatory neuropeptides or constricting extracerebral arteries effectively prevents and terminates migraine attacks, underscoring the importance of peripheral mechanisms. More than mere vasodilation, this hypothesis posits that chemical agents, including potassium released by vascular smooth muscle cells, might precipitate migraine onset. The resulting mechano-chemical stimulus might activate perivascular nociceptors and ascending trigeminal pain signaling, ultimately culminating in generation of a migraine attack.

Introduction

Migraine is a preval‎ent and disabling neurological disorder characterized by recurrent attacks of moderate to severe headache, often accompanied by photophobia, phonophobia, nausea, and vomiting [1, 2]. About one-third of people with migraine experience aura—transient neurological disturbances, most commonly visual, that precede or accompany the headache [3]. Despite extensive research, the precise mechanisms underlying migraine pathogenesis remain incompletely understood [2]. Traditional views have oscillated between vascular and neuronal hypotheses [4, 5], but emerging evidence stresses the need for a more integrated concept.

In the mid-20th century, Harold G. Wolff proposed the vascular hypothesis, suggesting that migraine arises from intracranial vasodilation leading to headache [6]. This theory was, in part, based on the throbbing quality of migraine pain and observations that vasoconstrictive agents provided relief [6, 7]. While influential, the vascular hypothesis faced limitations, as it could not fully explain the plethora of neurological symptoms associated with migraine.

Subsequent research shifted focus toward neuronal mechanisms [5]. One prominent theory involves cortical spreading depression (CSD), a wave of neuronal and glial depolarization propagating across the cerebral cortex, associated with migraine aura [8]. Alternative neuronal hypotheses propose that migraine attacks result from functional oscillations within the brain stem or hypothalamus, affecting pain modulation pathways [9, 10]. These concepts highlight the role of neuronal hyperexcitability and neurotransmitter imbalances [5]. Yet, they often lack convincing explanations for the peripheral symptoms of migraine and the efficacy of peripherally acting treatments.

In 1979, Moskowitz and colleagues introduced the trigeminovascular hypothesis, providing a more compelling framework [11]. This hypothesis posits that activation of the trigeminovascular system (TVS) is central to the pathogenesis of migraine pain [11]. The TVS comprises the trigeminal nerve and its axonal projections to intracranial blood vessels and the meninges [12]. The release of vasoactive signaling molecules, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP), leads to neurogenic inflammation, intracranial vasodilation, and sensitization of meningeal nociceptors [12]. Importantly, the trigeminovascular hypothesis views intracranial vasodilation not as a primary cause but as a consequence of neurogenic inflammation and nociceptor activation [11]. The vasodilation is thus considered a surrogate marker rather than a direct initiator of migraine pain.

Building on these concepts, the vessel-to-neuron trigeminovascular hypothesis integrates vascular changes and neuronal activation within the TVS, proposing that intracranial vasodilation can directly initiate migraine attacks through activation of meningeal nociceptors [2]. This hypothesis suggests that mechanical and chemical stimuli resulting from intracranial vasodilation activate perivascular trigeminal and upper cervical nerve endings, leading to the release of signaling molecules that mediate migraine pathogenesis.

By considering intracranial vasodilation as both a cause and an effect within the migraine cascade, this hypothesis provides a unified model that accounts for clinical observations, experimental evidence, and therapeutic advents. The purpose of this review is to introduce and discuss the vessel-to-neuron trigeminovascular hypothesis, summarizing current evidence, and discussing its implications for migraine research.

The trigeminovascular system: anatomical and physiological foundations of migraine

The pathogenesis of migraine is intricately linked to the anatomy and physiology of the TVS [12]. Understanding this system provides fundamental insights into how vascular changes might directly influence nociceptor activity, leading to migraine attacks.

Intracranial vasculature and innervation

The intracranial vasculature, particularly the meningeal arteries, is densely innervated by nociceptive fibers originating from both the trigeminal nerve and upper cervical spinal nerves (C1-C3) [13–15]. These fibers lie in close proximity to blood vessels, positioning them ideally to detect and respond to vascular changes [16]. The convergence of trigeminal and upper cervical afferents in the trigeminocervical complex (TCC) facilitates bidirectional communication and cross-sensitization, contributing to the manifestation of headache and the often-associated neck pain in migraine [13, 14]. From the second-order neurons in the TCC, nociceptive signals are relayed to third-order neurons within the thalamus, which then project to the somatosensory cortex, insula, and other brain regions, culminating in the perception of migraine pain [12, 17].

Nociceptors and receptors

Meningeal nociceptors primarily comprise unmyelinated C fibers and thinly myelinated Aδ fibers, which detect noxious stimuli and express a variety of receptors and ion channels [18]. Key among these are transient receptor potential (TRP) channels, which respond to thermal and chemical stimuli [19]. In addition, mechanosensitive Piezo channels detect mechanical stretch and deformation of the cellular membrane [20]. The presence of these channels enables meningeal nociceptors to respond to a wide array of stimuli, including chemical, and mechanical changes associated with vascular dynamics.

Preclinical studies have demonstrated that exposure to migraine-triggering agents sensitizes meningeal nociceptors to mechanical stimuli [15, 21, 22]. As a result of this sensitization, these nociceptors exhibit an exaggerated response to mechanical stimuli [15, 21–23], possibly contributing to the throbbing nature of migraine pain and its exacerbation during routine physical activity. This phenomenon is further underscored by the resemblance of symptoms between meningeal irritation—such as that observed in meningitis—and migraine [24], highlighting the pivotal role of meningeal nociceptors in migraine pathophysiology.

Classical and contemporary neurosurgical studies have provided empirical support for the role of intracranial vasculature in migraine pathogenesis [6, 25, 26]. Pain-sensitive intracranial structures, including the meninges and its blood vessels, have been identified, whereas the brain parenchyma itself is largely insensitive to pain [27]. In awake patients undergoing neurosurgical procedures, direct stimulation of perivascular meningeal sites elicits headache ipsilateral to the stimulus [6, 25]. The patients described this headache as deep and aching, accompanied by nausea—symptoms that closely mirror those experienced during migraine attacks [6, 25]. Furthermore, mechanical distension of intracranial arteries induces throbbing pain that ceases almost immediately upon the cessation of the distension [26]. These clinical observations suggest how vessel-to-neuron signaling might contribute directly to migraine pain.

Mechanisms of vessel-to-neuron signaling

Causality in migraine does not necessitate that a factor is either sufficient or necessary to trigger an attack in all instances. Analogous to how smoking is a major cause of lung cancer without being the sole determinant, vessel-to-neuron signals might causally contribute to migraine attacks even though exceptions exist. The role of the intracranial vasculature in migraine is more nuanced than simple mechanical vasodilation; it involves both chemical and mechanical signals originating from vascular smooth muscle cells (VSMCs) within the walls of intracranial arteries [2, 28].

Mechanical and chemical activation of meningeal nociceptors

Intracranial vasodilation results in vessel distension, which mechanically might activate adjacent meningeal nociceptors. Mechanosensitive ion channels, such as Piezo, respond to membrane stretch and transduce mechanical forces into electrical signals [29, 30]. Upon activation, these channels facilitate the influx of cations, leading to depolarization of nociceptors and initiation of action potentials that propagate along the trigeminal pain pathway [20]. Ample evidence also implicates other mechanosensitive channels in migraine, including K2P channels and potentially also NMDA receptors [28], which recent findings suggest might possess mechanotransducive properties [31]. Yet other receptors modulate mechanosensitivity, including multiple members of the TRP and ASICs families that respond to noxious stimuli [28]. The aforementioned clinical observations support these mechanisms; distension of intracranial arteries during neurosurgical procedures trigger migraine-like pain in awake patients [6, 25, 26]. This direct activation underscores the potential for vascular distension to initiate nociceptive signaling.

Vasodilation is also associated with the opening of ATP-sensitive potassium (KATP) channels and large conductance calcium-activated potassium (BKCa) channels within the VSMCs [32, 33]. The activation of these channels leads to potassium efflux from VSMCs, increasing the extracellular potassium concentration in the perivascular space. Elevated extracellular potassium reduces the membrane potential threshold of nearby nociceptors, facilitating their depolarization and activation [34]. Recent evidence provides mechanistic support for this line of reasoning. Opening of KATPchannels with levcromakalim infusion activated ~ 70% of mechanosensitive meningeal nociceptors – the neurons considered responsible for migraine headache [35]. This was demonstrated in a study using direct, in-vivo single-unit electrophysiology recording from the trigeminal ganglion in rats, while relying on a design that closely mimicked human provocation studies [35]. This finding likely explains experimental studies demonstrating that pharmacological openers of potassium channels, including KATP channels and BKCachannels, can trigger migraine attacks in people with migraine [36, 37]. Conversely, blocking these channels attenuates pain responses in preclinical models [38].

During vasodilation, endothelial cells and VSMCs release various signaling molecules, including nitric oxide (NO) and prostaglandins [39, 40]. These mediators are known triggers of migraine attacks and potent dilators of intracranial arteries in people with migraine [41–43]. Furthermore, NO can enhance TRP channel activity, while prostaglandins lower the activation threshold of nociceptors [22]. The release of these substances can thus contribute to amplifying pain signals within the TVS system.

Collectively, these mechanical and chemical signals are interrelated and might act synergistically to activate perivascular nociceptors. Experimental disentanglement is challenging, but both pathways provide plausible mechanisms for vessel-to-neuron signaling in migraine pathogenesis.

Neurogenic inflammation and feedback loops

Neurogenic inflammation represents a pivotal mechanism in migraine pathogenesis, driven primarily by the activation of perivascular meningeal nociceptors [44]. Once activated, these nociceptors release a host of vasodilatory and pronociceptive substances, including CGRP, PACAP, and substance P [45, 46]. Collectively, these neuropeptides induce vasodilation, increase vascular permeability, and sensitize nociceptors to subsequent stimuli.

Concurrently, perivascular immune cells such as macrophages and mast cells can be activated by these neuropeptides, leading to the additional release of prostaglandins, histamine, and other pro-inflammatory mediators [47–50]. These agents further expand the inflammatory milieu by promoting vasodilation and enhancing nociceptor excitability, thereby contributing to migraine initiation and progression [22]. In this manner, a composite response emerges in which VSMCs, immune cells, and nociceptors interact reciprocally to sustain and amplify both vasodilation and nociceptor activity.

This process fosters a positive feedback loop wherein the recruitment of additional nociceptors perpetuates the neurogenic inflammatory response, causing it to intensify over time [4]. As a result, migraine headache may become self-sustaining, with increasing numbers of activated nociceptors releasing growing concentrations of pro-inflammatory and pro-nociceptive mediators. By augmenting vasodilation and lowering nociceptor activation thresholds, this loop underscores the importance of vessel-to-neuron signaling in both the initiation and maintenance of migraine.

Emerging evidence supporting a causal role of intracranial vasodilationMigraine provocation models

Pharmacological agents that cause dilation of intracranial arteries have been shown to induce migraine attacks in people with migraine. Notably, a 20-minute continuous intravenous administration of CGRP, NO donors (e.g., nitroglycerin), and PACAP triggers migraine attacks in people with migraine but not in healthy adults [51]. This specificity supports the causal role of intracranial arterial dilation and vessel-to-neuron signaling in migraine pathogenesis, as the same dose and infusion duration of these molecules do not elicit similar responses in healthy adults.

This approach implicates specific molecular targets in migraine pathogenesis and allows for the study of induced migraine attacks akin to spontaneous ones. Identification of molecular migraine triggers identified through randomized, double-blinded, placebo-controlled, crossover trials represent a gold standard for establishing causality in medical research. These models have been instrumental in demonstrating the role of endogenous neuropeptides (e.g., CGRP, NO, and PACAP) and intracellular signaling pathways involving cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in migraine [52].

Vascular effects of molecular migraine triggers

All identified molecular migraine triggers dilate cephalic and meningeal arteries, as demonstrated by magnetic resonance angiography and high-resolution ultrasonography [37, 53–60]. While some substances, such as NO donors and KATPchannel openers, dilate cerebral vessels, endogenous peptides like CGRP and PACAP-38 primarily dilate extracerebral arteries due to poor blood-brain barrier penetration, suggesting that their peripheral action is sufficient to induce migraine attacks [54, 56]. Moreover, migraine-inducing substances, such as CGRP, do not induce pain when administered subcutaneously in either cephalic or extracephalic regions [61, 62], and some possess anti-nociceptive effects when administered centrally [63]. This indicates that their migraine-inducing effects are not mediated through direct neuronal action but involve vascular mechanisms.

Vessel-to-neuron signaling mechanisms

Our hypothesis is that the migraine-inducing potential of all identified molecular triggers is related to their common effects on VSMCs within the walls of meningeal arteries (Fig. 1). In this unified cascade, neuropeptides bind to G-protein-coupled receptors on VSMCs, increasing intracellular cAMP levels [64–66]. Elevated cAMP leads to the phosphorylation and opening of specific potassium channels, including KATP channels and BKCachannels [67]. Notably, these channels can also be activated via a parallel cGMP–dependent pathway that mediates the effects of NO and soluble guanylate cyclase [68].

Fig. 1.

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Hypothesized Vessel-to-Neuron Signaling in Migraine Pathophysiology. Both endogenous and exogenous migraine-inducing agents converge on a shared signaling cascade in vascular smooth muscle cells (VSMCs) of intracranial arteries, particularly within the meninges. At the cell surface, neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) bind to their receptors and stimulate adenylate cyclase (AC), thereby increasing intracellular levels of cyclic adenosine monophosphate (cAMP) [64–66]. Cilostazol, another potent migraine trigger, further elevates cAMP by inhibiting phosphodiesterase-3 (PDE3)–mediated degradation [69]. In a parallel pathway, glyceryl trinitrate donates nitric oxide (NO) to activate soluble guanylate cyclase (sGC), which raises cyclic guanosine monophosphate (cGMP) [68]. Sildenafil sustains this effect by blocking phosphodiesterase-5 (PDE5), preventing cGMP breakdown [70]. Elevated levels of cAMP and cGMP then activate protein kinases that phosphorylate and open potassium channels, including ATP-sensitive (KATP) and BKCachannels, leading to potassium efflux [67, 68]. This efflux is believed to depolarize perivascular trigeminal afferents, generating nociceptive signals that travel via the trigeminal ganglion to second-order neurons in the spinal trigeminal nucleus, and subsequently to third-order neurons in the thalamus. From the thalamus, nociceptive information projects to cortical regions such as the primary somatosensory cortex, insula, and visual cortex, ultimately giving rise to the perception of migraine headache [17] AC, adenylate cyclase; ADM, adrenomedullin; AMY, amylin; PDE3, phosphodiesterase-3; PDE5, phosphodiesterase-5; PGE2, prostaglandin E2; PGI2, prostaglandin I2; sGC, soluble guanylate cyclase; VIP, vasoactive intestinal peptide

The culmination of these intracellular events is the efflux of potassium ions, resulting in hyperpolarization of the VSMC membrane and subsequent dilation of intracranial arteries. Pharmacological inducers, such as KATP channel openers and BKCachannel openers, act directly on these potassium channels, facilitating potassium efflux [37, 71]. Given that all migraine-inducing substances exert their effects on extracerebral arteries—particularly the meningeal arteries—but only some affect cerebral arteries, it is likely that these vascular events unfold predominantly in the extracerebral vasculature [37, 53–60].

The resulting vasodilation and associated potassium efflux are hypothesized to lead to depolarization of adjacent perivascular nociceptive afferents, initiating pain transmission along the trigeminovascular pathway. As mentioned before, this vessel-to-neuron signaling can involve two principal mechanisms. First, vasodilation causes mechanical stretching of the vessel wall, providing a mechanical stimulus that activates nearby nociceptors. Second, the efflux of potassium from VSMCs increases the extracellular potassium concentration in the perivascular space. This elevation in extracellular potassium might depolarize nearby nociceptors by shifting their resting membrane potential toward threshold, facilitating action potential generation [2]. This chemical form of vessel-to-neuron signaling is compelling, considering that direct application of potassium ions to nociceptors is a well-established method of inducing depolarization [34].

Case example calcitonin gene-related peptide signaling

A plausible example of vessel-to-neuron signaling in migraine pathogenesis involves the CGRP pathway. Intravenous infusion of CGRP reliably induces migraine attacks in people with migraine [72–74], underscoring its pathogenic role. Notably, pre-treatment with erenumab—a monoclonal antibody targeting the CGRP receptor—reduces CGRP-induced migraine attacks to 27% (10 of 37 participants), compared with 53% (20 of 38 participants) in those receiving placebo [75]. Despite this robust effect, erenumab did not prevent migraine attacks induced by cilostazol, a phosphodiesterase 3 inhibitor that elevates intracellular cAMP downstream of the CGRP receptor [75]. Erenumab also failed to prevent migraine attacks induced by sildenafil [76], which acts via the cGMP-dependent pathway, or by levcromakalim, a KATPchannel opener [77]. These observations suggest that erenumab mediates its therapeutic benefits in VSMCs within the walls of intracranial arteries. Once downstream effectors of cAMP or other parallel routes are activated, CGRP receptor blockade alone cannot prevent migraine attack initiation.

Interestingly, erenumab has shown no efficacy in trigeminal neuralgia, a disorder characterized by recurrent attacks of severe facial pain that arise from direct irritation of the trigeminal nerve [78]. In a recent randomized, double-blind, placebo-controlled trial, erenumab failed to reduce pain intensity or attack frequency in participants with trigeminal neuralgia when compared to placebo [79]. This contrast with erenumab’s success in preventing migraine attacks highlights the distinct pathophysiological mechanisms underlying the two disorders. Whereas trigeminal neuralgia is thought to result from direct nerve irritation, migraine likely depends on CGRP-mediated intracranial vasodilation and subsequent perivascular meningeal nociceptor activation. Thus, the absence of benefit in trigeminal neuralgia further underscores the intracranial vasculature’s importance in migraine pathogenesis. If CGRP-receptor blockade is insufficient to mitigate trigeminal pain arising from purely neural irritations, yet effectively prevents migraine attacks, it supports the notion that migraine involves a critical vessel-to-neuron signaling component in its pathogenesis.

Case example vascular KATP channel modulation

Another compelling example of vessel-to-neuron signaling in migraine arises from the role of KATP channels. Historically, opening these channels was considered analgesic, as preclinical pain models showed that KATP channel opening could hyperpolarize neurons and diminish their excitability [80–82].

However, mounting evidence has revealed the opposite outcome in migraine provocation models. KATP channel openers can potently induce migraine attacks in people with migraine [36], pointing to an alternative mechanism centered on VSMCs. KATP channel opening leads to hyperpolarization of VSMCs and thus promotes vasodilation [32]. This vasodilation, coupled with increased potassium efflux, might explain findings that opening of KATP channels activate meningeal nociceptors [35]. In support, intravenous infusion of a KATP channel opener selective for neurons alone does not induce migraine attacks in people with migraine [83]. Moreover, preclinical data has demonstrated that vascular KATP channel openers are essential for both arterial dilation and headache-like behaviors induced by KATP channel openers and NO donors [38]. These results further underscore how vessel-to-neuron signaling plays an important role in migraine pathogenesis.

Case example vasoactive intestinal polypeptide signaling

A notable aspect of migraine attack induction involves not only the magnitude of vascular changes but also their duration. One of the most compelling examples of this concept derives from vasoactive intestinal polypeptide (VIP), a peptide with potent yet short-lasting cranial vasodilatory effects [58, 84]. When a 20-minute intravenous infusion of VIP is administered to people with migraine, it produces only a brief dilation of cranial arteries and results in low migraine induction rates (0–18%) [84]. However, extending the infusion to 120 min elevates the migraine attack induction rate to an impressive 71%, coinciding with a sustained vasodilatory response [58].

This dramatic escalation underscores how prolonged vasodilation might transform what could otherwise be a subthreshold phenomenon into a full-blown migraine attack. The extended VIP infusion effectively mimics the vascular effects observed with other established molecular migraine triggers, such as CGRP and PACAP [54, 56]. The difference might, in part, be related to VIP’s anti-inflammatory effects on mast cells [85], whereas PACAP-38’s ability to degranulate mast cells is thought to contribute to both prolonged vasodilation and migraine induction. Such evidence further supports the broader argument that vessel-to-neuron signaling, characterized by sustained vasodilation and subsequent nociceptor activation, is central to migraine attack generation.

Case example pituitary adenylate cyclase-activating polypeptide

Although a 20-minute intravenous infusion of VIP induces only transient vasodilation, the related neuropeptide PACAP-38 produces a more sustained dilation of cranial arteries [56]. This prolonged effect may explain PACAP-38’s strong migraine-inducing potential, as even a brief 20-minute infusion triggers migraine attacks in up to 58% of individuals with migraine [51]. The role of vasodilation in this process is further supported by evidence that early administration of sumatriptan—a known cranial vasoconstrictor—significantly reduces the incidence of PACAP-38–induced migraine attacks [86]. Recent findings also show that PACAP-38 activates meningeal nociceptors, possibly through indirect vascular mechanisms such as persistent dilation of meningeal arteries [87]. Notably, this nociceptor activation was blocked by dural application of lidocaine, implicating the dura mater as a key site of PACAP-38’s migraine-generating action [87]. Collectively, these observations suggest that prolonged meningeal vasodilation might be a critical mediator of migraine attacks.

Lateralization of pain corresponds to vascular changes

Evidence from neuroimaging studies supports the idea that vascular events drive trigeminal nociceptor activation in migraine [88]. Some studies report that vasodilation occurs on the pain side during spontaneous migraine attacks. For example, one study using magnetic resonance angiography demonstrated that people with unilateral headache exhibited dilation of intracerebral arteries on the pain side [88]. Another study using ultrasound found decreased blood flow velocity in the middle cerebral artery (MCA) on the headache side, suggesting lateralized vascular changes [89].

Similar observations have emerged from migraine provocation models. During CGRP-induced migraine attacks, both the middle meningeal artery (MMA) and MCA dilated ipsilaterally in people with unilateral headache, and bilaterally in those with bilateral headache [90]. Notably, CGRP alone does not dilate the MCA when given intravenously [54], implying that the observed dilation reflects processes tied to the induced migraine attack.

However, not all findings point in the same direction. In a study investigating PACAP-38–induced migraine attacks, arterial diameters did not differ between the painful and non-painful sides, and the cervical intracarotid artery even showed reduced diameter [56]. This study might have been underpowered to detect subtle lateralized changes. Another investigation of nitroglycerin-induced migraine attacks likewise found no difference in vasodilation between the painful and non-painful sides, nor an overall increase compared with placebo [91]. Despite these discrepancies, several lines of evidence suggest that cranial vasodilation often localizes to the side of migraine pain, supporting the argument that vessel-to-neuron signaling plays a causal role in migraine pathogenesis.

Therapeutic implications blocking vessel-to-neuron signaling

Triptans and ergot alkaloids—two commonly used serotonergic agents for migraine—might derive part of their therapeutic efficacy from their vasoconstrictive properties [92]. In contrast, the 5-HT1F agonist lasmiditan, which lacks vasoconstrictive activity, demonstrated lower efficacy than triptans in a recent network meta-analysis and was associated with more frequent central side effects [93]. Despite this limitation, lasmiditan likely suppresses neurogenic inflammation, thereby also indirectly mitigating vessel-to-neuron signaling [94].

As mentioned above, molecular triggers induce dilation of cranial arteries in migraine provocation models. Interestingly, a study investigating PACAP-38 found that sumatriptan’s vasoconstrictive effect reversed this dilation and prevented the onset of migraine attacks [86]. Likewise, sumatriptan exhibited comparable vasoconstrictive effects following CGRP administration [49].

Another clear indication of vascular involvement in migraine emerges from treatments that target vasodilatory neuropeptides. Indeed, blocking the CGRP pathway with monoclonal antibodies or gepants has proven effective for both acute and preventive migraine treatment [95–97]. Human experimental data further support this notion by showing that erenumab—a monoclonal antibody directed against the CGRP receptor—attenuates vasodilation and reduces migraine induction in people with migraine who receive intravenous CGRP infusion [75]. Moreover, a recent phase II trial has demonstrated that a monoclonal antibody targeting the PACAP ligand was superior to placebo in preventing migraine attacks [98]. Notably, this same antibody prevented dilation of the cranial arteries following PACAP-38 infusion in healthy adults [99]. By contrast, an antibody targeting the neuronal PAC1 receptor, rather than vascular PACAP-responsive receptors, failed to prevent migraine attacks [100].

It is also important to note that both monoclonal antibodies and gepants cross the blood–brain barrier only to a minimal extent because of their size and hydrophilicity [101, 102]. Consequently, they likely exert their primary effects outside the CNS, where inhibiting vessel-to-neuron signaling might underlie their therapeutic efficacy.

Integration with cortical spreading depression and aura

In spontaneous migraine attacks, an important trigger is aura and its neural substrate, cortical spreading depression (CSD)—a wave of neuronal depolarization that gradually spreads across the cerebral cortex [103]. In the wake of this depolarization, a host of nociceptive and inflammatory mediators are released, which may, in turn, sensitize and depolarize meningeal nociceptors [104, 105]. These mediators also exert pronounced vascular effects, initiating transient constriction followed by prolonged dilation of dural arteries [103]. The interplay between chemical effects of CSD and mechano-chemical vascular signaling might provide the input for subsequent nociceptor activation and migraine headache. Interestingly, some research suggests that the relationship between CSD and nociceptor activation might be bidirectional. In a recent open-label study, CGRP was capable of inducing aura in 38% of patients with migraine with aura [106]. This implies that CGRP might act through vascular pathways to induce trigeminal activation that eventually reaches the visual cortex, providing an excitatory stimulus capable of initiating CSD.

Complementing the established trigeminovascular hypothesis

The vessel-to-neuron trigeminovascular hypothesis builds upon and complements the traditional TVS hypothesis. While the latter emphasizes neurogenic inflammation as a primary driver, the vessel-to-neuron hypothesis highlights intracranial vasodilation as an initiator of migraine attacks [2]. Recognizing intracranial vasodilation as both a cause and effect creates a more comprehensive understanding of migraine pathogenesis.

Unified Pathophysiological ModelTrigger exposure

Various internal and external factors, such as stress, hormonal fluctuations, environmental stimuli, CSD, and vasodilatory agents, initiate vascular changes [52, 103, 107].

Vasodilation initiation

These triggers cause dilation of intracranial arteries, leading to mechanical and chemical alterations in the vascular environment [37, 53–60].

Vessel-to-Neuron signaling

Vasodilation activates trigeminal nociceptors through mechanical stretch of mechanosensitive channels and increased extracellular potassium levels.

Neurogenic inflammation

Activated nociceptors release neuropeptides (e.g., CGRP, substance P), causing further vasodilation, vascular permeability, and recruitment of immune cells [44, 47, 48].

Peripheral sensitization

Ongoing vessel-to-neuron signaling and neurogenic inflammation sensitize peripheral nociceptors, enhancing responsiveness to stimuli [22].

Central sensitization

Sustained peripheral input leads to central neuronal hyperexcitability, contributing to chronic migraine patterns [15, 108].

Migraine attack manifestation

The combined peripheral and central sensitization culminates in a migraine attack, characterized by the typical headache and associated symptoms.

Conclusions

In summary, the vessel-to-neuron trigeminovascular hypothesis integrates intracranial vasodilation and trigeminal nociceptor activation into a coherent model of migraine pathogenesis. By recognizing vasodilation as both a trigger and a downstream effect, it reconciles vascular and neuronal theories within a single framework. This approach clarifies the potency of pharmacological migraine triggers and the efficacy of peripherally acting treatments. Ultimately, targeted disruption of vessel-to-neuron signaling might offer new avenues for preventing and treating migraine attacks.

Response to Karsan & Goadsby The Journal of Headache and Pain, 2025 [109]

The question of migraine pathogenesis continues to pivot on a long-standing dichotomy: central neural origin versus meningeal (i.e., peripheral) initiation. In their critique of the vessel-to-neuron trigeminovascular hypothesis, Karsan and Goadsby advocate for a CNS-centric model of migraine initiation, assigning primacy to a plethora of non-headache symptoms. While rhetorically polished, their claims are undermined by conflicting empirical evidence, methodological weaknesses, and conceptual oversights.

They begin by drawing a linguistic distinction between pathogenesis (cause) and pathophysiology (process), as if causality were merely an abstract debate rather than a scientific question. Yet, if meningeal vasodilation—induced by well-characterized agents—initiates a cascade that reproducibly results in a migraine attack, the evidence for a causal relationship is both compelling and robust.

What follows is our point-by-point response to Karsan and Goadsby’s core claims—clarifying misconceptions and reaffirming the vessel-to-neuron trigeminovascular hypothesis as the most coherent and empirically supported model of migraine pathogenesis.

Premonitory symptoms: nonspecific and inconsistent

Karsan and Goadsby build their central-origin thesis on the premise that premonitory symptoms—fatigue, mood changes, yawning, food cravings—predict imminent migraine attacks. This premise, however, collapses under empirical scrutiny.

A 2022 meta-analysis found that only 29% of individuals with migraine report any premonitory symptoms—the vast majority do not [110]. Among those who do, symptoms are highly variable and commonly observed in people with tension-type headache or no headache disorder at all [110, 111]. Fatigue affects more than 20% of the general population [112]; yawning occurs up to 20 times daily in healthy individuals [113, 114]. These are everyday phenomena, not reliable predictive markers.

Moreover, diary studies often show that patients record headache or neck pain during the supposed premonitory phase [110, 115, 116], directly contradicting the ICHD-3 definition of this period as pain-free [1]. If patients cannot reliably distinguish the prodrome from the headache phase, the use of premonitory symptoms to identify migraine attack initiation is fundamentally compromised.

Ultimately, Karsan and Goadsby’s logic rests on a flawed assumption: that premonitory symptoms require a central origin. Yet symptoms such as nausea, vomiting, and photophobia are also present in disorders of clearly peripheral etiology—including meningitis and subarachnoid hemorrhage [24, 117–119]. These features are not exclusive to CNS dysfunction. Likewise, allodynia is a normal physiological response that arises around sites of peripheral injury [120, 121].

Inferring causation from temporal correlation risks conflating coincidence with origin. CNS symptoms might reflect the brain’s response to peripheral events —but they do not define the origin of the disease.

Neuroimaging of the premonitory phase: methodologically fragile, biologically ambiguous

Karsan and Goadsby rely heavily on neuroimaging studies suggesting activation in CNS structures—particularly the hypothalamus—prior to headache onset. However, many of these studies suffer from methodological limitations that undermine their conclusions.

Several involved small sample sizes (often fewer than 10 participants), liberal statistical thresholds, and post hoc region-of-interest selection [9, 10, 122–124]. One often-cited study identified activation in 26 brain regions—a pattern more plausibly attributed to statistical noise than to a biologically coherent response [9].

Even when experimentally induced by agents like nitroglycerin, premonitory symptoms often follow mild headache [9, 41, 124]. In such cases, central activation observed on imaging is more plausibly interpreted as a downstream response to peripheral nociceptor activation—not as the initiating event. Functional neuroimaging, therefore, might illustrate involvement in the migraine process, but it does not establish the site of origin. In contrast, the vessel-to-neuron hypothesis identifies a specific initiating mechanism: meningeal vasodilation followed by nociceptor activation, setting the migraine cascade in motion.

Provocation studies: meningeal vasodilation as the universal precursor

The most decisive body of evidence comes from human provocation studies. Every identified migraine-inducing peptide—adrenomedullin, amylin, CGRP, PACAP, VIP—produces meningeal vasodilation and does not cross the blood–brain barrier in meaningful quantities [51, 56, 90, 125–128]. Yet these agents consistently trigger migraine attacks in individuals with migraine, but not in healthy volunteers.

In contrast, non-vasodilatory agents such as endothelin fail to provoke migraine despite systemic effects [129]. This asymmetry is not only statistically significant—it is causally meaningful. Vasodilatory agents likely activate mechanosensitive and chemosensitive nociceptors embedded in meningeal vessels—nociceptors primed to respond to vascular stretch, ionic shifts, and neuropeptide signals. Dismissing vessel-to-neuron signaling on the basis that migraine headache lacks pulse-synchrony is akin to rejecting fire as the cause of smoke because the smoke doesn’t always rise in a straight line. The absence of perfect temporal alignment does not negate causality—it reflects the inherent complexity of downstream biological responses.

To date, no pharmacologic agent has induced migraine in humans without involving meningeal vasodilation. Comparable causal evidence for a CNS-centric model remains absent.

Therapeutic evidence: peripheral blockade, durable efficacy

If migraine initiation was centrally-driven, effective treatments should require CNS penetrance. Yet most potent preventives—monoclonal antibodies against CGRP and its receptor—do not cross the BBB in meaningful amounts [130]. Their robust efficacy likely arises from inhibiting peripheral vessel-to-neuron signaling in the meninges.

Agents like gepants and lasmiditan, though non-vasoconstrictive, act on peripheral terminals to inhibit neuropeptide release and downstream inflammatory cascades [131–133]. Ubrogepant, notably, aborts attacks when administered during the presumed premonitory phase—before pain onset—despite very limited evidence of CNS penetration [134, 135].

This pharmacologic pattern strongly supports the notion that peripheral inhibition can abort migraine attacks, even those processed centrally. If migraine originated purely in the CNS, such treatments would not work. The fact that they do—reliably and across diverse patient populations—renders the CNS-centric hypothesis pharmacologically untenable.

Pathophysiological integration: peripheral initiation, central participation

Karsan and Goadsby present a false dichotomy: central versus peripheral. Migraine, like most pain disorders, is not defined by binaries—it is a systems-level disorder in which peripheral events trigger central cascades.

We propose that meningeal vasodilation activates perivascular afferents, triggering ascending signals to the trigeminocervical complex, hypothalamus, and cortex—where the migraine headache is processed, modulated, and ultimately perceived.

To date, no centrally acting agent, independent of peripheral mechanisms, has been shown to induce migraine attacks. In contrast, peripheral agents—including anti-CGRP antibodies and certain peptides—can consistently prevent or provoke migraine [51, 90, 130]. The evidence thus supports a model in which migraine attacks are initiated peripherally and then engage central pathways.

Conclusion: a causal model anchored in experimental data

The vessel-to-neuron trigeminovascular hypothesis is not the only model proposed to explain migraine pathogenesis—but it is, to date, the most experimentally anchored, mechanistically coherent, and clinically validated. It accounts for the ability of vasoactive agents to trigger migraine and the success of peripherally acting therapeutics that operate independently of CNS penetration.

While alternative hypotheses emphasize central initiation, none have matched the predictive or explanatory power of this model across provocation studies and therapeutic outcomes. Correlation, however suggestive, is not causation. The burden of proof lies not in theoretical appeal but in reproducible biology—and current data consistently implicate the meninges and its vasculature.

The vessel-to-neuron trigeminovascular hypothesis offers a compelling roadmap: a structured, testable framework through which future research can clarify the initiation, propagation, and modulation of migraine attacks. As with any scientific model, its value will be determined empirically—through verification, refinement, or falsification. Ultimately, progress in understanding migraine pathophysiology will be driven not by theoretical preference, but by empirical rigor.

We thank our colleagues for sharing their perspectives. Rigorous, evidence-based discourse is vital for advancing the science of headache disorders—and for improving patient care.

Acknowledgements

Figures were created using BioRender.

AbbreviationsBKCa  channel

large conductance calcium-activated potassium channel

cAMP

cyclic adenosine monophosphate

cGMP

cyclic guanosine monophosphate

CGRP

calcitonin gene-related peptide

CSD

cortical spreading depression

TVS

trigeminovascular system

KATP  channel

ATP-sensitive potassium channel

MCA

middle cerebral artery

MMA

middle meningeal artery

NO

nitric oxide

PACAP

pituitary adenylate cyclase-activating polypeptide

TCC

trigeminocervical complex

VIP

vasoactive intestinal polypeptide

VSMC

vascular smooth muscle cell

Authors’ contributions

R.H.C. wrote the first draft of the manuscript. H.A., and M.A. revised the manuscript for intellectual content.

Funding

This work was supported by the Lundbeck Foundation Professor Grant (R310-2018-3711 to M.A.).

Data availability

No datasets were generated or analysed during the current study.

DeclarationsCompeting interests

RHC has received personal fees from Teva, Pfizer, and Lundbeck, outside of the submitted work, has received honoraria from Neurotorium, and serves as section editor for the Journal of Pain Research. HA has received personal fees from AbbVie, Lundbeck, Pfizer, and Teva, outside of the submitted work. HA also serves on the Editorial Board of The Journal of Headache and Pain. MA has received personal fees from AbbVie, AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Pfizer, and Teva, outside of the submitted work; has received funding from Danish National Research Foundation, Lundbeck Foundation, Novo Nordisk Foundation, Novartis, and Lundbeck; serves as an associate editor for The Journal of Headache and Pain and associate editor for Brain; and serves on the editorial board of Neurotorium and has received honoraria.

Footnotes

Publisher’s Note

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