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neuromodulation이 중요한 term이구나!!
somato-visceral reflex
panic bird..
Implication of Neuromodulation Therapy by Electroacupuncture in.pdf
Abstract
Diabetes affects approximately 366 million individuals worldwide. Current pharmacological therapy is not perfect, and often is associated with adverse side effects. Acupuncture is used as an adjunctive treatment for a number of cardiovascular diseases. Chronic activation of the sympathetic nervous system has emerged as a key player in both the pathogenesis and progression of diabetes and metabolic syndrome.
- 당뇨는 지구상에서 3억 6천만명이 앓고 있는 질환.
- 최신 약물치료는 완벽하지 않고 때로는 부작용이 흔함.
- 침치료는 당뇨로 인한 심장혈관질환의 보조치료로 사용되고 있음.
- 교감신경계의 만성적 활성화는 대사질환과 당뇨의 진행과 병리에서 중요한 역할을 함.
Recent evidence indicates that the down regulation of central nitric oxide system leads to an increased renal sympathetic neural activity in diabetic rats. Our experimental studies have shown that electroacupuncture stimulation exerts sympathoinhibitory effects through activation of neurons in the arcuate nucleus, ventrolateral gray, and nucleus raphe to inhibit the neural activity in the rostral ventrolateral medulla. This brief review will discuss current knowledge of the effects of acupuncture on central nervous system and provide a perspective on the future of treatment of diabetes with this alternative medicine technique.
- 최신의 증거는 central 질소산화물 시스템의 하행조절이 신장 교감신경 활성을 야기함.
- 우리의 실험은 전침자극이 교감신경억제 효과를 보임. 이는 궁상핵, 중심회백질, 솔기핵에서 신경활성을 통해 rostral ventrolateral medulla에서 신경활성을 억제함.
- 이 리뷰논문은 침치료의 중추신경계에 대한 최신 지식과 당뇨병의 미래치료에 대한 전망에 대하여 토의함.
Introduction
Cardiovascular diseases are the most common cause of mortality
worldwide. Diabetes and hypertension are the major risk factors in
the development of cardiac hypertrophy, ischemic heart disease and
cardiac failure. The prevalence of diabetes increases with age, the
lifetime risk of developing diabetes approaches approximately 32.8%
for males and 38.5% for females [1]. Although treatment strategies [2-4]
targeting blood pressure, blood glucose, triglycerides, and low-density
lipoprotein cholesterol levels, along with lifestyle modifications have
been developed for this disease, treatment has not yet been perfected
and often is associated with adverse side effects.
Acupuncture is increasingly being accepted as an alternative
medical therapy in the United States. Manual acupuncture and its
potent alternative, electroacupuncture (EA), have been used in Asia
to treat a number of cardiovascular diseases including myocardial
ischemia, hypertension, and diabetes [5-7]. Many western physicians,
however, are reluctant to recommend acupuncture because its actions
in the treatment of diabetes remain controversial and because the
physiological mechanisms determining its response are largely
unknown to practitioners of western medicine. This brief review will
discuss current knowledge of the effects of acupuncture on central
nervous system and provide a perspective on the future of treatment of
diabetes with neuromodulation therapy such as EA.
Effects of Acupuncture on Diabetes in Experimental and Clinical Studies
Acupuncture is a 3000-year-old form of traditional Chinese
medicine that involves inserting needles at specific points along specific
meridians on the body to help treat diseases or pain that result from
imbalances of energy flow – ‘Qi’. The old acupuncture needles were
made of bronze, silver and gold. Today, most acupuncturists use
disposable stainless steel needles ranging in length (0.5–100 mm) and
gauge (0.12–0.30 mm). The depth of insertion varies from shallow
(1–2 mm) to deeper needling (50–60 mm). Variable methodology
can lead to different responses. For example, we have found that
electroacupuncture (EA) at the acupoints overlying the deep somatic
nerves exerts inhibitory effects on cardiovascular reflex responses,
while EA at those overlying the superficial nerves does not, suggesting
that point specificity exists in acupuncture treatment [8].
Recently, Peplow and Baxter performed a literature review on
electroacupuncture for control of blood glucose in diabetes [5]. Only
two studies were found using EA in human subjects, and they indicated
that electroacupuncture treatment lowered the blood glucose level in
obese patients and healthy subjects [9,10].
EA at 15 Hz for 30 minutes at Zusanli and Zhongwan’s acupoints
lowered the blood glucose level in fasted type I [11,12] and II diabetic
rats [13-15] as well as in fasting, normal rats [16]. Additionally, at these
same acupoints in hyperglycemic rats, EA resulted in decreased glucose
levels with elevated serotonin and endogenous opioids [11,17].
Interactions between the Autonomic Nervous System and Diabetes
The autonomic nervous system (ANS) - subdivided into the
parasympathetic and sympathetic branches - is crucial in regulating
glucose metabolism, thus mediating insulin secretion and absorption.
Studies have indicated that ANS impairment shares an interchangeably
causal relationship with diabetes.
One potential cause for elevated sympathetic activity is the genetic
polymorphism of beta-2 and -3 adrenoreceptor genes which have been directly associated with diabetes [18]. Sympathetic overactivity
may also be caused by the activation of the renin-angiotensin system,
contributing to hypertension in diabetic patients with chronic renal
failure [19]. Hyperinsulemia – a promoter of diabetes - can also trigger
the sympathetic system, increasing peripheral resistance and sodium
retention, increasing the risk for hypertension [19]. Moreover, cardiac
autonomic remodeling has also been demonstrated in diabetic rats [20].
Effective refractory period (ERP) typically shortens during sympathetic
stimulation, but unlike their healthy counterparts, the diabetic rats
displayed increased heterogenous atrial ERP and altered sympathetic
nerve histology (seen through tyrosine hydroxlase staining), thus
making them more susceptible to atrial fibrillation [20].
In retrospect, sympathetic overactivity causes the diabetic heart to
metabolize fatty acids instead of glucose, resulting in insulin resistance,
accumulation of lipid metabolites, increase in oxidative stress and
myocardial fibrosis [21]. These conditions decrease contractile capacity
in addition to abnormal diastolic and systolic function. To compensate
for this decrease in systolic function, the sympathetic nervous system
(SNS) is activated, initiating the diabetic heart to increase sympathetic
tone [21]. Furthermore, as epinephrine and norepinephrine are known
markers for sympathetic stimulation, elevated levels were found in
type I diabetic patients at high risk for chronic renal failure and the
progression of nephropathy [19]. In patients with type II diabetes,
sympathetic overactivity often contributes to insulin resistance,
stimulating skeletal muscle alpha- and beta-adrenergic receptors,
thus decreasing vasodilation and contributing to the development of
hypertension [22-25]. Hyperglycemia – directly linked with caloric
intake and body mass index – may explain further why the prevalence
of hypertension is higher in type II versus type I diabetic patients [26].
Considering the other opposing branch of the ANS, the
parasympathetic system stimulates pancreatic beta cells to secrete
insulin, whereas the sympathetic branch blocks the secretion of
insulin [23]. Vagal impairment can lead to sympathetic overactivity,
consequently promoting the reabsorption of sodium, increasing stroke
volume, heart rate and vascular resistance [19]. These all serve as risk
factors for cardiovascular disease and hypertension, viable players in
the formation of diabetes. Studies have also indicated that young adults
with impaired vagal reactivation tend to be more hyperinsulinemic
[23]. Additionally, chronic hyperglycemia promotes progressive
autonomic neural dysfunction in a manner paralleling the development
of peripheral neuropathy [27]. Interestingly enough, neuropathy is first
seen in the longest, autonomic neural fiber, the vagus nerve. This is
often seen in patients with cardiac autonomic neuropathy (CAN) [27].
The initial parasympathetic denervation and increased sympathetic
tone leads to nocturnal hypertension in diabetics, shortly followed by
sympathetic denervation or orthostatic hypotension. One of the earliest
symptoms of CAN is heart rate variability, but further progression of
this disease can lead to arrhythmias and sudden cardiac death [28].
Autonomic nervous system dysfunction underlies obesity by
decreasing insulin sensitivity and endothelial function while increasing
oxidative stress, myocardial fibrosis and causing hyperinsulemia
and hypertension; these are all mechanisms associated with the
development of diabetes [29]. However, the diabetic condition and
sympathetic overactivity are in close interaction, and possessing one
of the conditions exacerbates the other. It is clear that the sympathetic
nervous system plays a key role in both the pathogenesis and
progression of diabetes and metabolic syndrome (Figure 1).
Over the past decade, we have examined the central neural
regulation of sympathoexcitatory reflex by acupuncture in different
regions of brain, including the rostral ventral lateral medulla (rVLM),
hypothalamic arcuate nucleus (ARC), midbrain ventrolateral
periaqueductal gray (vlPAG) nuclei, medullary nucleus raphe pallidus
(NRP) and dorsal horn and intermediolateral column of the spinal
cord.
EA Inhibition of Neural Activity in the rVLM
The rVLM plays a critical role in the regulation of sympathetic
outflow and blood pressure (BP) [30]. Inhibition of neuronal
function in this nucleus results in significant BP decreases [31]. We
have demonstrated previously that both low frequency electro- and
manual acupuncture inhibit the pressor response as well as premotor
sympathetic neural firing in the rVLM [32]. Administration of
naloxone (non-specific, opioid receptor antagonist) or gabazine
(γ-aminobutyric acid or GABA type A receptor blocker) in the rVLM
abolishes EA modulation [33]. The rVLM is an important brain stem
region that processes somatic inputs during acupuncture stimulation.
When compared to cardiovascular inactive acupoints (LI 6-7, G 37-
39) over superficial afferent nerves, electrophysiological studies of
neuronal activity in the rVLM have shown that P 5-6 as well as LI 4-11
over the deep median and radial nerves provide more afferent input to
cardiovascular premotor sympathetic neurons in the rVLM [8]. This
observation likely explains why acupuncture over these deep nerves
most effectively lower elevated sympathetic outflow and BP.
Neurotransmitters in rVLM, ARC and vlPAG
Early studies suggested that EA attenuates the sympathoexcitatory
reflex responses through the release of opioids, GABA, nociceptin and
serotonin (or 5-hydroxytryptamine, 5-HT) in the rVLM [34-38]. We
have demonstrated that the EA inhibition of sympathoexcitatory reflex
response in cats is related to the activation of μ- and δ-, but not қ-opioid
receptors in the rVLM, suggesting that endorphins, enkephalins and
perhaps endomorphin, but not dynorphin are mainly responsible for
EA modulation of cardiovascular responses.
Immunohistochemical staining studies have demonstrated the presence of enkephalinergic neurons in the rVLM and endorphinergic
neurons in the ARC that project directly to the rVLM, and that both
neurotransmitter systems are activated by EA [39]. EA inhibits the
sympathetic reflex response through opioid-mediated inhibition of
glutamate in the rVLM [40]. Electrophysiological studies [41] have
determined that reciprocal excitatory glutamatergic (NMDA and
non-NMDA) projections exist between the ARC and vlPAG that may
participate in the EA inhibition of sympathetic nerve activity. This
reciprocal projection may include a cholinergic component in the ARC
but not in the vlPAG [42].
Furthermore, EA, through presynaptic endocannabinoid CB1
receptor stimulation, reduces the vlPAG release of GABA but not
glutamate during EA [43]. Reduced GABA disinhibits vlPAG neurons,
thus increasing their activity, which, in turn, through an action in the
NRP inhibits rVLM cardiovascular sympathetic neurons and related
sympathoexcitatory reflex responses [44]. Therefore, it is clear that
a variety of neurotransmitter systems underlie the cardiovascular
modulation of EA. This includes both excitatory and inhibitory
neurotransmitters, with their importance varying between the different
nuclei.
Long-Loop Pathway for EA Cardiovascular Modulation
The role of the hypothalamic ARC and its interaction with the vlPAG
and rVLM in the EA-cardiovascular sympathoexcitatory responses has
been extensively studied [8,37,45,46]. Microinjection of the excitatory
amino acid DL-homocysteic acid (DLH) into the ARC augments the
responses of vlPAG neurons, while microinjection of small volumes
(50 nl) of kainic acid (KA) causes a reversible depolarization blockade
that transiently deactivates arcuate neurons and decreases the vlPAG
responses to splanchnic nerve (SN) stimulation [37]. Additionally, EA
increases SN-evoked discharge of vlPAG neurons, a response that can
be blocked by microinjection of KA into the ARC. Microinjection of
DLH into the ARC, like EA, inhibits the sympathoexcitatory reflex
induced by application of bradykinin to gallbladder for approximately
30 min. Finally, microinjection of KA into the ARC blocks the
inhibitory influence of EA on the sympathetic pressor reflex. As such,
these results suggest that excitatory projections from the ARC to the
vlPAG appear to be essential to the inhibitory influence of EA on the
pressor reflex induced by SN and gallbladder afferent stimulation.
vlPAG-rVLM Projections
The vlPAG provides inhibitory input to premotor sympathetic
neurons in the rVLM to ultimately reduce sympathetic outflow and
reflex elevations in BP [46]. Direct axonal projections from the vlPAG
to the medulla have been documented in tract tracing studies [47].
However, a vlPAG projection to the raphe, in particular the nucleus
raphe obscurus (NRO), also exists and has been thought to form an
indirect pathway from the vlPAG to the rVLM that is involved in
the EA-cardiovascular response [48]. However, recent studies have
suggested that the NRP, located more ventrally than the NRO or the
nucleus raphe magnus, contains more cells activated during median
nerve stimulation with EA at the P 5-6 acupoints, as judged by the
concentration of c-Fos labeling [49]. Chemical blockade of the NRP
with KA or kyneurnic acid transiently reverses activation of neurons in
the rVLM during stimulation of the vlPAG as well as EA modulation
of visceral excitatory reflexes [50]. Furthermore, the NRP inhibits
rVLM activity, including activity of bulbospinal premotor sympathetic
neurons. Serotonin projections from the raphe acting on 5-HT1A
receptors in the rVLM complete the vlPAG-NRP-rVLM circuit to
modulate cardiovascular activity [50]. Thus, an indirect connection
from the vlPAG to the rVLM involving a serotonergic connection
between the NRP and the rVLM plays an important role in the longloop
modulation of cardiovascular sympathetic outflow during reflex
visceral stimulation. These studies do not eliminate the possibility that
direct projections between the vlPAG and the rVLM also might serve a
functional role in EA-cardiovascular modulation. The direct or indirect
projections from the vlPAG to the rVLM complete the long-loop
pathway and provide an important source for the inhibitory influence
of EA on rVLM premotor neurons and ultimately sympathoexcitatory
cardiovascular responses [48].
ARC-rVLM Projections
As noted previously, neurons in the vlPAG receive convergent input
from a number of somatic nerves stimulated during EA, as well as from
the ARC. Bilateral microinjection of KA into the rostral vlPAG partially
reverses rVLM neuronal responses and cardiovascular inhibition during
DLH stimulation of the ARC. Conversely, depolarization blockade of
the caudal vlPAG completely reverses arcuate-evoked rVLM responses
[48]. In parallel studies, we have observed that arcuate neurons can be
antidromically activated from the rVLM and that arcuate perikarya
are labeled with a retrograde tracer microinjected into the rVLM [48].
Many neurons from the arcuate that project to the rVLM are activated
by EA stimulation (c-Fos-positive) and they frequently contain
opioid peptides, particularly β-endorphin [51]. As such, the vlPAG,
particularly the caudal vlPAG, appears to be required for inhibition
of rVLM neuronal activation by the ARC and subsequent EA-related
cardiovascular activation. However, direct projections from the ARC
to the rVLM, likely serve as an important source of β-endorphin since
this projection contains this opioid peptide [48]. This latter observation
is consistent with our earlier anatomical study showing that cells in
the rVLM contain enkephalin but not β-endorphin [51]. Hence, EAcardiovascular
responses that result from the action of β-endorphin
on μ-opioid receptors located on rVLM sympathoexcitatory premotor
neurons depend on this hypothalamic-medullary projection [52].
Role of Spinal Cord in Acupuncture-Cardiovascular
Response
The spinal cord processes somatic and visceral reflexes as well as
outputs from the central nervous system to effector organs involved
in cardiovascular reflex regulation [53]. Anatomical and physiological
studies indicate that the dorsal horn of the spinal cord serves as a major
center for EA-induced analgesia [54,55]. Both low- and high-frequency
EA at Zusanli (St 36) acupoint increase Fos immunoreactive neurons
in the superficial laminae (I and II) in the dorsal horn of the spinal
cord [55]. Since opioid or nociceptin-like immunoreactivity is present
in the spinal sympathetic nuclei (i.e. intermediolateral colum, IML)
[56,57], we have considered the possibility that EA also influences the
neurotransmission between the brain stem and the IML [58]. In this
regard, our studies have found that both opioid and nociceptin reduce
the response to rVLM-induced sympathoexcitation, indicating that the
two peptides can regulate sympathetic outflow [59,60]. In addition,
there has been a suggestion that descending pathways from the brain
stem (presumably to the dorsal horn of the spinal cord) may influence
the segmental processing of somatic inputs during EA [61,62]. Afferent
stimulation can modulate sympathetic activity through the inhibition
of excitatory interneurons [63]. Furthermore, somatic stimulation
can elicit excitatory and inhibitory responses in both IML and dorsal
horn interneurons, depending on the dermatome stimulated [64].
These interneurons appear to form important links in the spinal cord
circuitry involved in autonomic control [65]. Taken together, these results indicate that opioid and nociceptin play a role in the processing
of spinal cord interneuron activity in the EA response. However, spinal
circuits controlling the cardiovascular visceral reflex responses during
EA require further elucidation.
Summary
EA inhibits the sympathetic outflow by modulating the activity
of cardiovascular presympathetic neurons in the rVLM. Activation
of neurons in the ARC of the hypothalamus, vlPAG in the midbrain
and NRP in the medulla by EA can inhibit the activity of premotor
sympathetic neurons in the rVLM. Glutamate, acetylcholine, opioids,
GABA, nociceptin, serotonin, NO, endocannabinoids in the brain all
appear to participate in the EA sympathoinhibitory response (Figure
2). Since the ANS plays an important role in the glucose metabolism,
modulation of sympathetic outflow are presumed to be the mechanisms
underlying the hypoglycemic effects of acupuncture. Previous studies
have demonstrated that EA reduces the plasma glucose levels by
increasing insulin production and improves insulin sensitivity by
inducing secretion of endogenous β-endorphin [66] and serotonin
[67]. Lee et al. recently have shown that EA at ST36 acupoints induce
a hypoglycemic effect by stimulating the cholinergic nerve in diabetic
rats [68,69]. Taken together, these results provide a strong link between
the central acupuncture and the treatment of diabetes.
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