Neuromodulation: Technology at the Neural Interface Received: December 22, 2009

First revision: March 3, 2010

Accepted: May 7, 2010

(onlinelibrary.wiley.com) DOI: 10.1111/j.1525-1403.2010.00295.x

Mechanism of Acupuncture on Neuromodulation in the Gut—A Review

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Toku Takahashi, MD, PhD Introduction: Acupuncture has been used for treating various gastrointestinal (GI) diseases. However, the mechanism of acupuncture remains unclear. Methods: The aim of this article is to review the published literature on the mechanism of acupuncture on neuromodulation in the gut. Results: Acupuncture treatment involves the insertion of thin needles into the skin and underlying muscle and the subsequent stimulation of the needles manually or electrically. Thus, acupuncture stimulates the somatic afferent nerves of the skin and muscles. The somatic sensory information from the body is carried to the cortex area of the brain. Somatic sensory fibers also project to the various nuclei at the brain stem and hypothalamus. Via somato-autonomic reflex, acupuncture modulates various biomechanical responses, such as prokinetic, antiemetic, and anti-nociceptive effects. Conclusion: According to traditional Chinese medicine, “Acupuncture is believed to restore the balance of Yin and Yang.” This can be translated into the Western medicine terminology that “Acupuncture modulates the imbalance between the parasympathetic and sympathetic activity.” Acupuncture may be effective in patients with functional GI disorders because of its effects on GI motility and visceral pain. Keywords: Muscle contraction, neurostimulation, nociceptive pain, opioid, peripheral nerve stimulation, transcutaneous electrical nerve stimulation, vagal nerve stimulation Conflict of Interest: The author declared no conflicts of interest.

INTRODUCTION Acupuncture has been in practice in China for more than 3000 years. Acupuncture has been used for treating various gastrointestinal (GI) diseases (1,2), including gastroparesis (3,4), functional dyspepsia (5,6), irritable bowel syndrome (7–9), constipation (10,11), diarrhea (12,13), and visceral hypersensitivity (14). Acupuncture was first introduced to the American public in 1972. However, acupuncture has not been well accepted by the physicians in the Western countries. This may be due, in part, to the mysterious and unexplainable mechanisms of acupuncture. In this review, the possible mechanisms of acupuncture treatment are discussed from the view point of Western medicine, rather than through the concepts of traditional Chinese medicine.

ENERGY FLOW (QI) OR SOMATO-AUTONOMIC REFLEX?

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Energy Flow and Meridians—Concept of Traditional Chinese Medicine According to traditional Chinese medicine concepts, the energy force, known as Qi (pronounced Chee), runs through the body. This Qi energy enters the body through specific acupuncture points and flows to deeper organ structures, bringing life-giving nourishment of a subtle energetic nature. Meridians are classified on the basis of the direction in which Qi flows on the surface of the body. There are about 20 meridians, which include the 12 regular and 8 extraordinary meridians. www.neuromodulationjournal.com

A person’s health is influenced by the flow of Qi in the body, in combination with the universal forces of Yin and Yang. If the flow of Qi is insufficient, unbalanced, or interrupted, Yin and Yang become unbalanced and illness may occur (15). However, these ancient traditions/concepts of Qi and meridians have no counterpart in modern studies of chemistry, biology, and physics. To date scientists have been unable to find evidence that supports their existence. Acupuncture is believed to restore the balance of Yin and Yang. Acupuncture loci, also know as acupoints, are the skin needling points used for acupuncture treatment. In humans, more than 300 acupoints are located along the meridians. Acupoints are thought to be the specific points reflecting visceral conditions and organs (16). Despite the fact that the specific acupoints are used for treating specific symptoms and/or diseases, it is not fully understood how their specificity applies and how the needling at acupoints works. Ahn et al. conducted a systematic review of studies directly evaluating the electrical characteristics of acupuncture structures and

Address correspondence to: Toku Takahashi, MD, PhD, Research Service 151, Zablocki VA Medical Center, 5000 West National Avenue, Milwaukee, WI 53295, USA. Email: [email protected] Department of Surgery, Medical College of Wisconsin and Zablocki VA Medical Center, Milwaukee, WI, USA For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1

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ACUPUNCTURE ON NEUROMODULATION appropriate controls. There was no clear evidence to demonstrate the existence of acupuncture points or meridians. Present evidence does not conclusively support that acupuncture points or meridians are electrically distinguishable (17).

Somato-Autonomic Reflex Acupuncture treatment involves the insertion of thin needles into the skin and underlying muscle layer. In traditional acupuncture procedure, these acupuncture needles are twisted right and left at 0.5–1 second intervals. Most recently, acupuncture needles are stimulated by electricity under various frequencies of 1–100 Hz (Electroacupuncture, EA). Thus, the procedure may stimulate the somatic afferent nerves of the skin and muscles. It has been demonstrated that somatic afferents from the skin and muscle are involved in the control of various autonomic functions. In 1913, Lehman reported that electrical stimulation of the central part of the sciatic nerve inhibits intestinal motility and that the splanchnic nerve is responsible for mediating the inhibitory response in dogs (18). Electrical stimulations of the hind limb stimulate gastric motility via somatic afferents in cats (19). More details of neural mechanisms of cutaneo-GI motility reflexes have been studied in rats during the period from 1975–1980. Sensory stimulation of the abdominal skin by pinching inhibits gastric motility by increasing gastric sympathetic efferent nerve activity in rats (20,21). In contrast, pinching the hind paw enhances gastric motility by exciting gastric vagal efferent nerve activity (22). In healthy humans, transcutaneous electrical nerve stimulation applied to the hand and abdomen reduces antral motility (23). These studies provide good evidence indicating the importance of cutaneous input in autonomic control of GI functions. The nucleus tractus solitarius (NTS) is the primary brain stem relay for visceral information from cardiovascular, respiratory, and GI systems. In addition, recent studies indicate that the NTS also receives somatic afferent inputs (24,25). Electrophysiological study demonstrated that the NTS receives input from low- and highthreshold cutaneous mechanoreceptors. NTS neurons are activated by the rhythmic and sustained muscle stretch of the hind limb (26). Neurons of the NTS and the spinal cord were labeled by injection of neuroanatomical tracers to the acupoints of hind limb (ST-36) in rats (27). Acupuncture at the facial acupoints increases the number of c-Fos immunopositive cells in the NTS in rats (28). Therefore, it is highly likely that somatic stimulation induced by acupuncture is conveyed to the NTS. The NTS is adjacent to the dorsal motor nucleus of vagi (DMV) and both compose the dorsal vagal complex. The dorsal vagal complex integrates vago-vagal reflex, which plays a major role in regulation of GI function (29,30). The NTS neurons also project to the rostral ventrolateral medulla (RVLM) of the brain stem (31–33). The RVLM neurons provide drive to the sympathetic preganglionic neurons in the intermediolateral nucleus of the spinal cord (34). Thus, once NTS neurons are stimulated by acupuncture autonomic nerve function is altered via the activation of the DMV and/or RVLM.

MECHANISM OF ACUPUNCTURE ON GI FUNCTION

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Effects of Acupuncture on GI Motility in Normal Conditions Among the more than 300 acupoints, several special points have been used for treating GI symptoms. Acupoint of ST-36 is one of the most effective points, with a wide range of effects for analgesia,

immunity, homeostasis, and GI disorders. ST-36 is located near the knee joint approximately 10 mm lateral to the anterior tubercle of the tibia in humans. Acupoint of ST-25 is used for treating chronic colitis and diarrhea (35,36). ST-25 is located 50 mm lateral to the umbilicus on the abdomen in humans. It is well known that acupuncture has regional specific effects. Acupuncture at the hind limbs stimulates gastric motility (37–39), while acupuncture at the abdomen inhibits gastric motility (37,39,40) in rats. The excitatory gastric responses to the hind limb are abolished by bilateral vagotomy in rats (37–39). In contrast, the inhibitory gastric responses to abdomen are abolished by sympathetic nerve dissection in rats (37,40). Acupuncture on the hind limbs increases vagus discharges, while acupuncture on the abdomen increases sympathetic discharges in rats (37,39). Sympathetic and parasympathetic activity can be evaluated by heart rate variability (HRV) analysis in conscious animals noninvasively. The power in the high frequency (HF) band of HRV represents parasympathetic activities in rats (41,42) and humans (43). In contrast, the power in the low frequency (LF) band of HRV represents sympathetic activities in rats (41,42) and a combination of sympathetic and parasympathetic activities in humans (43), respectively. Electroacupuncture at ST-36 decreases, while EA at ST-25 increases the ratio of LF/HF in rats (44). These studies suggest that inhibitory gastric responses to the abdomen are mediated via sympathetic nerves, while the excitatory gastric responses to the hind limb are mediated via the vagus nerves. However, the mechanism of regional differences of acupuncture points has not been fully studied. It has been suggested that acupuncture-evoked afferent input converge in several nuclei in the brain stem, such as the RVLM (45,46), the NTS (26–28,47), the DMV (38,47), and Barrington’s nucleus (48). Electroacupuncture at ST-36 increases the number of c-Fos immunopositive cells at the DMV and the medio-caudal and caudal part of the NTS, while EA at ST-25 increases the number of c-Fos immunopositive cells at the RVLM and medio-caudal part of the NTS in rats. This suggests that somatic afferents activated by EA at ST-36 is conveyed to the medio-caudal and caudal NTS and stimulates the DMV neurons. In contrast, somatic afferents activated by EA at ST-25 is conveyed to the medio-caudal NTS and stimulates the RVLM neurons (49). Thus, EA at ST-25 inhibits gastric motility via the somatosensory–NTS–RVLM–sympathetic efferent pathway. In contrast, EA at ST-36 stimulates gastric motility via the somatosensory– NTS–DMV–parasympathetic efferent pathway. In addition to the NTS, DMV, and RVLM, acupuncture may activate some other nuclei in the brain. EA at PC-6 activates neurons in the arcuate (ARC) nucleus and periaqueductal gray (PAG) and inhibits the activity of RVLM, suggesting the existence of ARC-PAG-RVLM neuronal pathway in mediating EA inhibition on visceral excitatory cardiovascular reflexes (50). Even though the study focuses on the cardiovascular system (50), similar mechanisms might be utilized to produce the effects of EA on GI motor function. It has been shown that the PAG is responsible for mu receptor agonist- and neurotensin-induced inhibition of intestinal transit (51). The verification of neural pathway may contribute to the mechanisms of the regional difference of acupuncture in regulating GI motor function. Migrating motor complex is well characterized by the appearance of GI contractions in the interdigestive state. In a canine study, combined EA at ST-36 and PC-6 (wrists) enhances the interdigestive gastric migrating motor complex (52). EA at ST-36 and PC-6 accelerates gastric emptying and increases the regularity of gastric slow waves in the stomach (53).

TAKAHASHI The stimulatory effect of EA on gastric motility is associated with increased vagal activity in dogs (53). There has been no direct evidence reported that EA stimulates vagal activity in humans. Acupuncture at ST-36 increases the plasma pancreatic polypeptide levels in humans (54). As pancreatic polypeptide release is dependent on vagal activity, this supports the notion that acupuncture at ST-36 may stimulate the vagal activity in humans. EA at ST-36 accelerates colonic transit and stimulates distal colonic motility in rats (48,55). The stimulatory effect of EA on distal colonic motility is mediated via the activation of Barrington’s nucleus of the pons and parasympathetic-pelvic nerves (48).

Effects of Acupuncture on GI Motility in Stressful Conditions It is well known that various stressors delay gastric emptying via hypothalamic corticotropin-releasing factor (CRF). Released CRF inhibits parasympathetic activity and/or stimulates sympathetic activity, resulting in delayed gastric emptying (56,57). Animal studies demonstrated that acupuncture improves various stressinduced physiological responses (58–60). Delayed gastric emptying induced by restraint stress or central administration of CRF is restored by EA at ST-36 in rats. The stimulatory effect of EA on stress-induced delay of gastric emptying is antagonized by pretreatment with intracisternal (ic) injection of a glutamate receptor antagonist. This suggests that EA at ST-36 stimulates glutaminergic transmission at the brainstem resulting in improvement of stress-induced delay of gastric emptying in rats (61). Heart rate and LF component are increased in response to restraint stress, suggesting increased activity of sympathetic tone during stress loading. EA at ST-36 attenuates the elevated LF component and increases the HF component in response to stress loading (42). This suggests that EA at ST-36 stimulates parasympathetic activity and inhibits sympathetic activity under the restraint stress. According to traditional Chinese medicine, “Acupuncture is believed to restore the balance of Yin and Yang.” This can be translated into the Western medicine terminology that “Acupuncture modulates the imbalance between parasympathetic and sympathetic activity.”

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Effects of Acupuncture on Emesis Acupoint of PC-6 has been used for nausea and vomiting. PC-6 is located in the groove caudal to the flexor carpi radialis and cranial to the superficial digital flexor muscles. A committee of the National Institute of Health published a report on the indications of acupuncture in November 1997. The summary of the consensus statement indicates that there is clear evidence that acupuncture treatment is effective on postoperative and chemotherapy-induced nausea and vomiting (62). In 1987, Dundee et al. reported that acupuncture at PC-6 decreases cisplatin-associated nausea and vomiting (63). A clinical study also demonstrated that EA at PC-6 significantly inhibits the postoperative nausea and vomiting after the surgery (64,65). Electroacupuncture at PC-6 reduces gastric tachyarrhymia in vection-induced motion sickness in healthy volunteers (66). Combined acupuncture at ST-36 and PC-6 increases the percentage of regular slow waves, resulting in the normalization of arrhythmia in healthy humans (67). However, the mechanisms of antiemetic effect of acupuncture need to be elucidated. Level of plasma arginine vasopressin is rapidly elevated in response to diverse emetic stimuli such as www.neuromodulationjournal.com

motion stimuli (68) and anticancer drugs (69,70). Intravenous injection of vasopressin results in vomiting and retching in humans (68,71) and dogs (72,73). Acupuncture at ST-36 and PC-6 attenuates symptom scores of emesis induced by vasopressin infusion in dogs (73). Retrograde propulsive movement is highly associated with the frequency of retching and vomiting. EA at PC-6 reduces the frequency of retrograde propulsive movement induced by vasopressin in dogs (74). Opioids have dual effects: an antiemetic effect as well as an emetic effect. It has been shown that central opioid plays a major role in mediating antiemetic effect (75). The emetic effect is mediated via the chemoreceptor trigger zone (CTZ), whereas the antiemetic effect is mediated via the vomiting center (75–77). The CTZ is contained in the area postrema on the caudal margin of the forth ventricles. As area postrema has no blood brain barrier, naloxone methiodide (a peripheral opioid antagonist) can antagonize the emetic effect of opioid mediated via the CTZ. In contrast, the vomiting center is deeply located beneath the solitary tract of the caudal brain stem. Both the emetic and antiemetic effects of opioid can be blocked by naloxone, because naloxone can cross the blood brain barrier (77). Naloxone hydrochloride, but not naloxone methiodide, abolishes the antiemetic effect of EA at PC-6 in dogs (74). This suggests that the antiemetic effect of EA at PC-6 is mediated via the central opioid pathway.

Effects of Acupuncture on Visceral Pain It has been well demonstrated that the analgesic effect of acupuncture is mediated by an endogenous opioid pathway (5,78). The painful sensation induced by rectal distension is attenuated by EA at ST-36 in dogs. The anti-nociceptive effect of EA at ST-36 is abolished by pretreatment with naloxone, but not naloxone methiodide. This suggests that EA at ST-36 reduces visceral pain via a central opioid pathway (79). Opioid-induced anti-nociception is mediated by a pathway from the PAG to the various brain nuclei. Recent research has documented that opioids are likely to exert direct effects on PAG projection neurons through both delta- and mu-opioid receptors (80). EA can induce the expression of opioid peptides and opioid receptors in the CNS (81,82). Using functional magnetic resonance imaging, acupuncture modulation in CNS structures can be studied noninvasively in humans, allowing for comparison with animal studies. The PAG and cortical areas responds to manual acupuncture at LI-4 (hand), while sham acupuncture results in reduced levels of the PAG and cortical activity (83). EA at ST-36 modulates activity in the substantia nigra, nucleus raphe magnus, locus ceruleus, nucleus cuneiformis, and the PAG. Activation in the ventrolateral PAG is greater for EA at ST-36, compared with sham EA (84).

CONCLUSION The mechanisms behind the beneficial effects of acupuncture can be explained by Western medicine terminology. Acupuncture stimulation of somato sensory neurons activates various nuclei at the CNS, including the NTS, DMV, RVLM, and PAG, etc. Activation of the NTS, DMV, and RVLM modulates the imbalance between sympathetic and parasympathetic activity. Opioid released from the PAG is involved in mediating antiemetic and anti-nociceptive effects of acupuncture.

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ACUPUNCTURE ON NEUROMODULATION Functional GI diseases are common in the general population with a reported prevalence of 25–40%. Functional GI disorders are the multifactorial disorders in which the pathophysiological mechanisms are variably combined in different patients. The motor dysfunction of GI tract and visceral hypersensitivity are considered to be especially important factors. Acupuncture may be effective in patients with functional GI disorders because acupuncture has been shown to alter GI motility and visceral pain.

Authorship Statements Dr. Takahashi designed and conducted the study, including data collection and data analysis. He prepared the manuscript.

How to Cite this Article: Takahashi T. 2010. Mechanism of Acupuncture on NeuRomodulation in the Gut—A Review. Neuromodulation 2011; 14: 8–12

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COMMENTS The author provides interesting insights about mechanisms and pathways underlying acupuncture treatment for gastrointestinal diseases. He describes mechanisms of acupuncture by using the research and terminology that is more common in Western medicine. While the author focuses on gastrointestinal diseases, acupuncture may utilize similar mechanisms and pathways to treat not only visceral pain but also autonomic reflexes. This is based on the work of Longhurst’s team (Li et al., 2009) and Taché et al. (1990) who showed that the periaqueductal gray is involved in autonomic reflexes as well as the visceral pain described in the present article. In fact, Taché et al. showed that the periaqueductal gray matter is a site that is responsible for mu receptor agonist- and neurotensin-induced inhibition of intestinal transit. The report by Longhurst’s team (2009) also shows that the ventrolateral periaqueductal gray is required for arcuate nucleus inhibition of rostral ventrolateral medullary neuronal activation and subsequent activation of electroacupuncture-related cardiovascular reflexes. Even though their study focuses on the cardiovascular system, similar mechanisms might be utilized to produce the effects of electroacupuncture on gastric function. Robert D. Foreman, PhD Professor and Chair Department of Physiology College of Medicine University of Oklahoma Health Sciences Center Oklahoma City, OK, USA 1. Li P, Tjen-A-Looi SC, Guo ZL, Fu LW, Longhurst JC. Long-loop pathways in cardiovascular electroacupuncture responses. J Appl Physiol 2009 Feb;106(2):620–630. 2. Taché Y, Garrick T, Raybould H. Central nervous system action of peptides to influence gastrointestinal motor function. Gastroenterology 1990 Feb;98(2):517–528.

*** Acupuncture does not work to cure specific organic diseases. The mechanism of acupuncture intervention is best described as neuromodulation of disordered function back to the normal physiological status. This article touches the basics of acupuncture. JS Han, MD Peking University Neuroscience Research Institute Beijing, China *** The effects of acupuncture on the modulation of autonomic nervous system dysfunction may be a relevant basis for the treatment of the patients with functional gastrointestinal disorders. The author of this review makes a case for the use of acupuncture in patients with visceral pain and functional GI disorders by “connecting the dots” between numerous basic science studies and likely indications for the use of acupuncture in humans. Leonardo Kapural, MD, PhD Director, Clinical Research, Pain Management Department Cleveland Clinic Foundation Associate Professor of Anesthesiology CCLCM of Case Western University Cleveland, OH, USA Comments not included in the Early View version of this paper.

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