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Acupuncture and Related Techniques for Pain Relief and Treatment of Heroin Addiction
source:Mary Ann Liebert 2020-12-22 [Research]
Mechanisms and Clinical Application

Song-Ping Han  and Ji-Sheng Han

 

Published Online:16 Dec 2020https://doi.org/10.1089/acu.2020.1485

 

 

Abstract

A neurochemical hypothesis of acupuncture analgesia suggests that the pain relief effect of acupuncture is primarily due to activation of a central endorphin system. It has been shown that the primary afferent sensory fibers, a mesolymbic neural circuit, and a descending inhibitory pathway are critical in acupuncture analgesia. The therapeutic effects of electroacupuncture (EA) and related techniques, such as transcutaneous electroacupoint stimulation (TEAS), are frequency-dependent: different frequencies of EA activate different brain regions and release different neuropeptides. EA and TEAS have been used successfully to treat heroin addiction. Activation of endorphin gene expression and release by TEAS can explain the dramatic attenuation of withdrawal syndrome and prolongation of retention time during and after detoxification treatment in patients who are addicted to heroin. However, repeated EA at high intensity should be avoided because it can induce a gradual loss of the analgesic effect. Opioid-receptor desensitization occurs and is manifested as decreased ligand-binding affinity and second-messenger detachment. Repeated large doses of morphine induce morphine tolerance. Cross-tolerance between morphine and EA suggests similar underlying mechanisms. Recent studies have demonstrated that excessive activation of cholecystokinin (CCK), an antiopioid peptide, appears to be responsible. CCK-receptor subtype B (CCKBR) and opioid μ-receptor are co-expressed in the dorsal-horn neurons. Activation of CCKBR promotes formation of heteromerization of morphine-receptor and CCKBR. Interaction of the third transmembrane domain between the 2 receptors resulted in the reduced binding affinity of the opioid receptor.

Introduction

Acupuncture research was promoted following President Richard M. Nixon's visit to China in 1970 and by a 1997 National Institutes of Health consensus conference on acupuncture, which was followed by growing support of research in this field. Evidence of this can be seen in a large spike in the number of scientific articles published related to acupuncture since that time. A vast amount of evidence from this research has accumulated; this research suggests that the effect of acupuncture is mediated by primary afferent fibers, the central endorphinergic neurons, and the descending inhibitory pathways. Yet, it is still unknown why some patients—as many as 20%—do not respond to acupuncture analgesia. This is likely due to several reasons, including: (1) individual differences in the ratio of released amount of endogenous opioids and antiopioid peptide cholecystokinin; (2) whether the optimal parameters of electroacupuncture (EA) stimulation are applied. EA analgesia appears to be parameter-specific, releasing different neuropeptides that activate different brain regions. The correct parameters need to be identified according to each disease. It is likely that inappropriate treatment may turn a potential responder into a nonresponder.

Discussion

The effects of EA have been found to be frequency-dependent. Studies—both in human beings and experimental animals—have shown that EA at different frequencies releases different kinds of neuropeptides and transmitters, producing different therapeutic effects. Human studies have also shown frequency-dependent peptide release, with different endorphins released by EA of different frequencies. EA also accelerates the release of endogenous opioids. A mesolimbic neural circuitry seems to play a critical role in acupuncture analgesia. Primary and supplementary motor areas of the brain are involved in EA analgesia.1 Han and colleagues have developed neurochemical maps of EA analgesia that involve communication between the cerebral cortex and the dorsal horn.2

Prolonged use of morphine and/or EA produces profound desensitization of the μ-opioid receptors (MORs). MORs and cholecystokinin (CCK)–8 receptor, subtype B (CCKBR), are co-expressed in dorsal-root ganglion (DRG) neurons.3 CCK-8 has potent antiopioid activity in the dorsal-horn neurons (the pain pathway). CCK-8 antagonizes MOR activity at the second-messenger level and reduces the binding affinity of MORs. Activation of CCKBR antagonizes the cyclic adenosine monophosphate response and intracellular-calcium response to MORs activation. The binding affinity of MOR is reduced in the presence of the CCKBR agonist.

A co-immunoprecipitation study in human embryonic kidney (HEK) 293 cells with stable co-expression of MOR and CCKBR demonstrated that the activation results in heteromerization of CCKBR and MOR and decreased binding affinity of MORs via interaction that occurs at the third intracellular loop. This overexpression of CCK-8 in the CNS might be related to the mechanisms of acupuncture tolerance caused by frequent and prolonged EA treatments. Excessive EA promotes CCK release and EA tolerance.3,4 High innate CCK levels in some individuals might be responsible for the nonresponse to EA treatment observed in clinical settings. This is an important finding for understanding the nonresponse data in clinical trials.

EA treatment has profound therapeutic effects on acute withdrawal syndrome in patients who are addicted to heroin. Han and colleagues have shown that transcutaneous electroacupoint stimulation (TEAS) reduced the total scores of patients in acute heroin-withdrawal syndrome significantly, including muscle pain, craving, anxiety, chilling, and sweating. The results of a retention trial showed that in the TEAS group, 33% of subjects remained drug-free 9 months after the detoxification program. In contrast, no-one in the MOCK TEAS group remained drug-free after the same period of time. This might be related to increased expression of enkephalin and dynorphin genes in the nucleus accumbens as shown in an EA-treated rat model of morphine dependence. Techniques to assess these factors in vivo, in humans, are needed.2

Author Disclosure Statement

No financial conflicts of interest exist.

Funding Information

The study was partially supported by a grant from The Chinese Ministry of Science and Technology (2019YFC1712004).