The Effect of Acupressure
4.5 The Mechanism of Acupressure on Chemotherapy-induced Nausea
A literature search was conducted in CINAHL, MEDLINE, and PubMed using the key words acupressure, mechanism, nausea, and P6/PC6/Neiguan/Neikuan.
Some researchers did not use PC6 as a keyword instead they used Neiguan or Neiguan which is the Chinese name for PC6. No study has been published reporting the mechanism of acupressure on nausea. Another literature search was conducted in CINAHL, MEDLINE, and PubMed using the key words acupuncture, mecha- nism, nausea, and P6/PC6/Neiguan; acupuncture, P6/PC6/Neiguan, and substance P/serotonin/histamine (H1 and H2)/dopamine/acetylcholine/opioids. Clinical trials published in peer-reviewed journals between 1 January 1992 and 31 December 2011 were searched. Inclusion criteria were: (1) studies using acupuncture as the sole intervention for nausea for one group; and (2) studies written in English.
Exclusion criteria were: (1) studies using moxibustion, nerve stimulators, or laser acupuncture; (2) studies not using any biophysical measure on outcomes; (3) studies not using PC6; and (4) unpublished papers and abstracts. Acupuncture is a therapy using needles to stimulate acupuncture points, while acupressure is a therapy using fi ngers. EA uses a small electric current that is passed between pairs of acupuncture needles. From three databases, 27 studies were retrieved from PubMed, 29 from CINAHL and MEDLINE, and four from hand searching. After applying inclusion and exclusion criteria, 18 studies were eligible for review.
According to the previous systematic reviews, acupuncture at PC6 in fl uences the autonomic nervous system by inhibiting sympathetic nerves and increasing para- sympathetic nerve activity (Abad-Alegria et al. 2001 ; Huang et al. 2005 ; Landgren et al. 2010 ) . Huang and his colleagues ( 2005 ) suggested that the relief of nausea and vomiting by acupuncture at the PC6 point can be explained by the parasympathetic nerves (largely mediated by the vagus nerve) which modulate heart and gut. The stimulation of the vagus nerve decreases heart rate and increases peristalsis of the gut. Vagus or vagal nerve is a cranial nerve that regulates talking, swallowing, gag re fl ex, and parasympathetic activity (McCance and Huether 2002 ) . Increased vagal activity is related to chemotherapy-induced nausea (Morrow et al. 2000 ) , while decreased vagal activity or injury to the vagus nerve is related to the delayed empty- ing and gastric re fl ux (Lindeboom et al. 2004 ) . These fi ndings suggest that normal parasympathetic activity may decrease nausea by increasing gastric emptying, while excessive parasympathetic activity may increase nausea by increasing gag re fl ex.
4.5.1 Autonomic Nervous System
The autonomic nervous system consists of parasympathetic and sympathetic nerves (McCance and Huether 2002 ) . The parasympathetic nerves are located in both the central nervous system (CNS) and the peripheral nervous system (PNS). The para- sympathetic nerves function to save and restore energy. The parasympathetic nerves stimulate digestion and increase intestine motility and decrease heart rate, while sym- pathetic nerves slow digestion and motility (McCance and Huether 2002 ) . Huang and his colleagues ( 2005 ) reported that acupuncture at PC6 for 20 min decreased heart rate
measured by electrocardiogram compared to the control group (no acupuncture) in 111 healthy subjects. This fi nding suggests that acupuncture at PC6 modulates the imbalance of parasympathetic nerve, which is related to nausea.
4.5.2 Serotonin
Serotonin is a neurotransmitter involved with mood, anxiety, sleep induction, and intestinal motility. About 80–90% of serotonin exists in the enterochromaf fi n cells in the gut, and the remainder is made in serotonergic neurons in the CNS. Serotonin stimulates the emetic center and increases nausea (McCance and Huether 2002 ) . Electroacupuncture (EA) at Jianshi (PC5) and PC6 increased c-Fos immuno reactivity, neurons double-labeled with c-Fos, and either enkephalin or serotonin in all three midline medullary nuclei, especially in the nucleus raphe pallidus in six cats compared to cats with manual acupuncture ( p < 0.05). These results propose that the medullary raphe nuclei, particularly the nucleus raphe pallidus, process somatic signals during EA and participate in EA-related modulation of cardiovascular function through an opioid or serotonergic mechanism (Guo et al.
2008 ) . EA produces a synergism of the CNS with a direct impact on the uterus through increasing the release of b -endorphin and serotonin into the peripheral blood (Qu and Zhou 2007 ) . Acupuncture at PC6, Shenman (HT7), and Sanyinjiao (SP6) using Jin-3 needling therapy for 45 min, six days per week for six weeks, reduced plasma level of adrenocorticotropic hormone and platelet content of serotonin compared with the drug and needling group and drug only group in 86 patients with generalized anxiety disorder (Yuan et al. 2007 ) .
4.5.3 Cholecystokinin (CCK) and the Dorsal Vagal Complex
CCK is a polypeptide hormone secreted by the gastrointestinal mucosa. CCK stimulates the gallbladder to eject bile and the pancreas to secrete alkaline fl uid and CCK decreases gastric motility (McCance and Huether 2002 ) . Cholecystokinin-A receptors are involved in the induction of meal-like fullness and nausea associated with intraduodenal lipid and gastric distention (Feinle et al. 1996 ) . The dorsal vagal complex located in the brainstem (Charrier et al. 2006 ) controls the upper digestive tract (Rhoades and Bell 2009 ) . EA at PC6 and ST36 signi fi cantly accelerated gastric emptying and concurrently increased vagal activity assessed by the spectral analysis of the heart rate variability, suggesting a possible vagal mechanism in dogs with delayed gastric emptying induced by duodenal distention (Ouyang et al.
2002 ) . EA at PC6 and ST36 speeded up solid gastric emptying measured by scin- tigraphy in patients with gastroparesis (Xu et al. 2006 ) . EA at PC6 inhibited gastric distention-induced transient lower esophageal sphincter relaxation (gastric re fl ux), which is related to impairment of the vagus nerve in 12 cats (Lindeboom et al. 2004 ; Wang et al. 2007 ) .
4.5.4 Opioids
Endogenous opiates such as endorphins, dynorphin, and enkephalins are released into the blood as part of the response to stressful stimuli. Endorphins and enkephalins are widely distributed in the CNS and PNS. The CNS consists of the brain and the spinal cord, while the PNS consists of the somatic nervous system and the autonomic nervous system. High b -endorphin levels increase the pain threshold (McCance and Huether 2002 ) . Chemotherapy-induced nausea is related to decreased levels of opioids (National Cancer Institute 2012c ) . Li and his colleagues ( 2001 ) found that EA (1–2 mA, 5 Hz) at PC5 and PC6 for 45 min activated d - and m -opioid receptors in the rostral ventrolateral medulla in 12 cats. EA (2–5 Hz, 2–5 mA) at PC6 for 30 min reduced myocardial ischemia, measured by regional myocardial wall thickening. Intravenous and microin- jected naloxone into the rostral ventral lateral medulla prevented the EA–related response. Opioid m and d , but not k , receptors in the rostral ventrolateral medulla are responsible for the EA-related modulation of sympathetic out fl ow, suggest- ing that endorphins and enkephalins, but not dynorphins, are the neuromodula- tors involved in this response (Li et al. 2002 ) . EA (10 Hz) at PC6 for 60 min signi fi cantly reduced the number of episodes of retching and vomiting and sup- pressed retrograde peristaltic contractions compared to EA at weishu (BL21) or ST36 in seven dogs with vasopressin-induced emesis. The anti-emetic effect of EA was canceled by pre-treatment with naloxone but not naloxone methiodide.
It is suggested that the anti-emetic effect of acupuncture is mediated via the central opioid pathway (Tatewaki et al. 2005 ) . Naloxone methiodide is thought not to cross the blood-brain barrier and is used as a research tool to differentiate between central and peripheral sites of action for drugs acting on opioid receptors (Lewanowitsch and Irvine 2003 ) . EA (1–10 Hz) at Zhongfeng (LR4), PC6, and ST36 for 45 min increased b -endorphin levels compared to sham acupuncture (short stud instead of needles) in 40 participants with colorectal discomfort due to a colonoscopy (Leung et al. 2011 ) .
4.5.5 g -Aminobutyric Acid (GABA)
GABA is the most widespread neurotransmitter in the CNS (McCance and Huether 2002 ) . A lack of GABA or excessive GABA may cause nausea (Alstermark et al. 2008 ; Li and Akk 2008 ) . Gabapentin which increases GABA in the brain improved nausea in patients with chemotherapy-induced nausea (Guttuso et al. 2003 ) . EA (2 Hz, 2–4 mA) at PC5 and PC6 for 28 min reduced the release of GABA by 39% during EA and by 44% 15 min after EA in midbrain ventrolateral periaqueductal gray in rats (Fu and Longhurst 2009 ) . These fi ndings suggest that acupuncture at PC5 and PC6 modulates the imbalance of GABA which is related to nausea.
4.5.6 Catecholamine
Catecholamines such as epinephrine, dopamine, and norepinephrine are released at the medulla of the adrenal gland during the stress response (McCance and Huether 2002 ) . Especially, norepinephrine increases nausea by inhibiting gastrointestinal activity (McCance and Huether 2002 ; Dube et al. 2010 ) . EA (3 Hz, 0.2 ms pulses, 20 mA) at PC6 and Shaohai (HT3) for 30 min decreased blood pressure, heart rate, and plasma norepinephrine and epinephrine levels compared to the control group (Waiguan (TE5), Yinlian (LR11), and tail) in rats with immobilization stress (Yang et al. 2002 ) . EA (3 Hz, 0.2 ms pulses, 20 mA) at HT3 and PC6 for 30 min signi fi cantly reduced the expected increases in blood pressure, heart rate, and attenuated plasma levels of norepinephrine and epinephrine in rats with forced immobilization (Yang et al. 2002 ) .
4.5.7 Functional Magnetic Resonance Imaging
EA at PC6 activated the structures of the thalamus and the cortex, but deactivated the structures of the hypothalamus and hippocampus. The brain responses to EA existed in different areas of activation and deactivation despite stimulating the same acupuncture point (Ho et al. 2008 ) . Acupuncture at PC6 selectively acti- vated the left superior frontal gyrus, anterior cingulate gyrus, and dorsomedial nucleus of the thalamus compared to sham acupuncture and tactile stimulation.
This result suggests that the effect of acupuncture at PC6 might be mediated by the cerebellar vestibular neuromatrix (Yoo et al. 2004 ) . Acupuncture at PC6 activated typical pain-related areas which are the ventromedial and dorsolateral prefrontal cortex and perigenual anterior cingulate cortex on the cortical level. In the brainstem, needling sensation activated nuclei of the descending pain control system, in which a network of hypothalamus, periaqueductal gray, rostral ventro- medial medulla, and ventrolateral medulla was recognized as the source of the heart rate changes (Beissner et al. 2011 ) . The thalamus, cortex, prefrontal cortex, and cingulate cortex are the pathways of vagal afferents, which regulate nausea (Stern et al. 2007 ) . Acupuncture at PC6 activated the right nodule and right uvula of the cerebellum (Ren et al. 2010 ) . The common symptom of cerebellar disorder is nausea (Windle et al. 2001 ) .
4.5.8 Summary of Mechanism
There are several hypotheses regarding the pathways of acupuncture. When acupuncture stimulates the skin, somatic afferent nerves (Higashimura et al.
2009 ) , myelinated nerve fi bers (Han et al. 2003 ) , and polymodal receptors
(Kawakita et al. 2006 ) are activated. Myelinated fi bers contribute to the afferent input of the autonomic re fl ex adjustments during EA. Myelinated and unmyeli- nated fi bers are stimulated by EA, although more fi nely myelinated than unmy- elinated fi bers are activated by low frequency and low current stimulation (Tjen et al. 2005 ) . The polymodal receptors release neuropeptides as well as activate an axon re fl ex in the spinal cord (Zhao 2008 ) . The neuropeptides move to tissue and organs to repair functioning. Polymodal receptors have effects on the central neurons (McCance and Huether 2002 ) as well as peripheral nerve fi bers (Xu et al. 2006 ) . The signal moves via the spinal cord (Jiang et al. 2010 ) to the brain.
Signals from the brain move via efferent nerves to body systems (Fig. 4.4 ). The effect of acupressure on chemotherapy-induced nausea at PC6 can be explained by regulation of the autonomic system, regulation of CCK and the dorsal vagal complex, and the mediation of neurotransmitters such as serotonin, GABA, and catecholamine. Acupuncture at PC6 may activate different mechanisms accord- ing to different factors. Combination with other acupuncture points (Shiotani et al. 2004 ) , types of acupuncture (laser, electro, manual), the frequency and intensity of EA (Wang et al. 2005 ; Shen and Lai 2007 ) , depth of needling (Ceccherelli et al. 2002 ) , length and diameter of needles, manipulation methods of manual acupuncture (lifting, thrusting, twisting, and twirling) (Zaslawski et al. 2003 ) , duration and intervals between stimulation, individual differences such as genetic (Chae et al. 2006 ; Kim et al. 2007 ) or Sasang constitution (Lee et al. 2009 ) , disease status (Toma et al. 2011 ) or status of yin-yang and fi ve ele- ments (Ahn et al. 2010 ) , or positive/negative perception toward stimulation (Linde et al. 2007 ) can be factors that affect the response to acupuncture (Fig. 4.5 ).
Sasang constitutional medicine explains that personal variable responses to food and medicinal treatment can be explained by the body constitution typology.
Sasang constitutional medicine categorizes people into four body types (TaeYang, TaeEum, SoYang, SoEum) according to their temperaments, body shapes, and other general character features (Lee et al. 2010 ) .
Fig. 4.4 Pathway of acupuncture