Electroacupuncture Relieves Pain During Alcohol Withdrawal

Abstract

Background: Alcohol use disorder (AUD) is one of the most prevalent chronic relapsing substance use disorders. The negative emotional state, including pain hypersensitivity that often occurs during abstinence, is believed to be a significant driving force for intensive seeking and relapse drinking. Studies have revealed that this may involve the inhibition of midbrain dopamine transmission and activation of the “antireward” system in the lateral habenula (LHb). Acupuncture has been proven effective in reducing pain and certain syndromes associated with AUD. There have been extensive studies conducted on acupuncture. However, the neuroanatomical basis behind acupuncture practice is still unclear.

Objective: To briefly describe recent research about acupuncture on pain, particularly those related to AUD.

Results: Preclinical studies found that electrostimulation of acupoints (electroacupuncture [EA]) effectively relieves hyperalgesia during withdrawal from chronic alcohol administration. This effect is mediated by the μ-opioid receptors in the LHb. Other studies revealed that the analgesic effect of EA could be mediated by mechanisms independent of the opioid system. Other evidence shows that acupuncture's strong anti-inflammatory effect also contributes to its analgesic effect.

Conclusion: Acupuncture could alleviate pain, including the pain in alcoholics, through mechanisms either dependent or independent of the opioid system. Since alcohol abuse causes inflammation, which is also a significant cause of pain, the strong anti-inflammatory effect of acupuncture may also contribute to its analgesic effect. Thus, acupuncture is a nonaddictive therapeutic choice for pain related to substance use disorders, including alcohol.

Introduction

Alcohol use disorder (AUD) is one of the most prevalent chronic relapsing substance-use disorders, affecting about 240 million people worldwide. AUD is a complex disease, with many factors contributing to relapse drinking. A significant contributor is the negative emotional state, which includes pain hypersensitivity and anxiety, which often occurs when the alcohol supply is stopped.

Alcohol and pain have a complicated relationship. Although acute administration of alcohol may reduce pain, chronic abuse of alcohol, particularly during abstinence, often results in pain hypersensitivity, which is believed to be a significant driving force for escalation of drinking and relapse.^1–3 Therefore, relieving pain hypersensitivity is an important therapeutic strategy for reducing consumption and relapse drinking in alcohol-dependent individuals. However, currently available therapeutics for AUD-related pain are limited and not satisfactory. Therefore, finding novel effective therapies is of paramount importance.

Acupuncture has been widely practiced in China and other Eastern countries for more than 3,000 years as a complementary and alternative therapy for various mental and physical disorders. In the past several decades, however, acupuncture has become an emerging new therapy in Western countries.^4,5

There have been extensive studies conducted on acupuncture. Clinical and preclinical studies have shown that acupuncture (both manual and electroacupuncture [EA], which applies electrical stimulation to acupoints to improve the efficacy), produces an analgesic effect on various pain, drug addiction, and affective disorders.^6–10 However, the neuroanatomical basis behind acupuncture practice is still not completely understood.

In this review, we focused on the mechanisms underlying acupuncture's effectiveness in relieving pain associated with alcohol abuse and withdrawal and suppressing alcohol drinking behaviors.

EA-INDUCED RELEASE OF ENDOGENOUS OPIOID PEPTIDES DEPENDS ON ITS FREQUENCY

Acupuncture (both manual and EA) can accelerate the production and release of opioid peptides in the nervous system. This effect was frequency dependent; that is, low-frequency (2 Hz) stimulation accelerated the production of enkephalin and endorphin, whereas high frequency (100 Hz) upregulated the level of dynorphin.^11,12 Many studies have identified μ and δ, but not κ opioid receptors as the mediator of acupuncture-induced analgesia.^13,14

NEURONAL ADAPTATION ON ALCOHOL ABUSE, AND THE ROLE OF THE LATERAL HABENULA

The neurobiologic mechanisms of AUD remain obscure. It is generally accepted that ethanol's addictive property is associated with its ability to increase the activity of dopaminergic (DA) neurons in the ventral tegmental area (VTA).^15,16 Although ethanol acutely activates mesolimbic DA neurotransmission, withdrawal from chronic ethanol leads to substantial decrements in VTA DA neuron activity^17–19 and extracellular DA levels in the nucleus accumbens (NAc).^20–22 It is believed that this DA hypofunction results in a dysphoric negative emotional state that leads drug seeking and taking behavior to restore DA to normal drug-naive levels.^22,23 However, the mechanism causing this DA hypofunction stays unclear.

Recently, the lateral habenula (LHb), a small epithalamic structure, has attracted much attention to abuse drugs because it can inhibit midbrain DA system activity. This inhibitory modulation is mediated indirectly via LHb's glutamatergic excitatory connection to the Gamma Aminobutyric Acid (GABA)-ergic neurons in the rostromedial tegmental nucleus, which directly inhibit VTA dopamine neurons. The LHb could act as a significant source of negative reinforcing signals to midbrain DA neurons through this circuit.

The LHb receives afferents from forebrain structures and sends projections to brainstem regions. These regions include well-known pain modulatory structures such as the periaqueductal gray, the raphe nuclei, and the VTA. μ-opioid receptors (MORs) are widely distributed in circuits that send and modulate nociceptive signals, and drugs acting on MORs have been considered the most powerful and broadly effective analgesics. Consistent with a previous report showing that MORs are richly expressed in the habenula,²⁴ the immunostaining data presented in a previous study revealed a dense MOR protein expression in the habenula, primarily distributed in the medial part of LHb and the lateral part of medial habenula.²⁵

The LHb also plays a critical role in processing nociceptive signals and generating aversive states. This is supported by the observation that LHb neurons were excited by aversive stimuli such as tail pinch,²⁶ sciatic nerve stimulation,²⁷ and air puffs to the face,²⁸ whereas lesions to the habenula could block the analgesic effect of electrical stimulation in the hypothalamus.²⁹ The high expression of MOR mRNA in the habenula provides further support to the LHb's role in pain.^30–32 A subset of LHb neurons was inhibited by [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, the MOR selective agonist, by inhibiting glutamate release into these cells.³³ MORs appear to act within the habenula, since analgesia is observed when MOR agonistmorphineis injected into the habenula.³⁴

Accumulating evidence suggests that excessive chronic ethanol use and withdrawal increases pain sensitivity.^35–37 As a type of subjective negative experience, pain may affect alcohol reinforcement and may facilitate the transition to alcohol abuse/addiction.¹

EFFECT OF ACUPUNCTURE ON RELAPSE DRINKING, THE ROLE OF MORs IN THE LHb

An earlier study assesses whether EA can alleviate hyperalgesia during ethanol withdrawal, and, if so, whether it achieves this effect via MORs located in the habenula. Specifically, the study examined the effect of EA on pain sensitivity in rats withdrawing from chronic ethanol drinking and the effect of blocking habenular MOR function on the efficacy of EA. The result showed that 2 Hz EA at ST36 alleviated hyperalgesia in the rats withdrawn from chronic alcohol administration. EA's analgesic effect was reduced by intrahabenula injection of naltrexone, an MOR antagonist, suggesting the involvement of habenular MORs.²⁵

EA's analgesic effect may contribute to its effect on reducing drinking, given that pain hypersensitivity during withdrawal was a significant driving force for the escalation of consumption and relapse drinking when alcohol drinking was resumed. Activation of LHb neurons inhibits VTA-dopamine neurons. LHb neurons are hyperactive during ethanol withdrawal.³⁸ EA increased the release of enkephalin, which binds to MORs in LHb neurons and inhibits LHb neurons.³⁹ This will lead to the activation of VTA-dopamine neurons through a mechanism of disinhibition. This finding shows the importance of LHb in the effect of EA on pain during alcohol withdrawal.

This finding is in general keeping with previous studies showing that EA reduces voluntary alcohol intake through the activation of MORs⁴⁰ and that EA at ST36 attenuated alcohol drinking behavior by enhancing dopamine levels in rats.⁴¹ The findings also support a study that revealed that acupuncture at HT7 prevented both the decrease of extracellular dopamine levels in the NAc during alcohol withdrawal and the increase in accumbal dopamine levels induced by ethanol challenge.⁴² Like the already mentioned studies, another study found that acupuncture decreased the firing rate of VTA-GABA neurons through activation of endogenous opioid systems.⁴³ Since VTA-dopamine neurons are under the inhibition of GABA neurons, acupuncture-induced inhibition of GABA neurons might activate dopamine neurons through a mechanism of disinhibition.

Given that MOR activation can inhibit glutamate release into LHb neurons,³³ we can speculate that EA-induced MOR activation may inhibit glutamate release in the LHb, which is increased during ethanol withdrawal.^38,39 This could then block descending nociceptive signals from the LHb to the periaqueductal gray,^44,45 and reduce pain. Nonetheless, further experiments are needed to test this possibility.

These studies show that EA at ST36 is an effective therapy to lessen pain during ethanol withdrawal, which may be mediated at least, in part, by MORs in the habenula. The results of this study improve our understanding of the specific mechanisms underlying EA therapy in AUD.^13,14,40,46

In support of the mentioned finding, a recent study found that acupuncture at acupoint HT7 (Heart 7, Shenmen) reduced symptoms such as anxiety in rats withdrawing from chronic alcohol administration through activation of β-endorphin neurons in the hypothalamus. These rats also drank less alcohol when they had access to alcohol. Acupuncture attenuates alcohol dependence through activation of endorphinergic input to the NAc from the arcuate nucleus.⁴⁷

ACUPUNCTURE INDUCES ANALGESIA VIA OPIOID-INDEPENDENT MECHANISMS

In addition to the opioid-dependent mechanism already mentioned, there is evidence that acupuncture can reduce pain via opioid-independent mechanisms.⁴⁸

EA Alleviates Hyperalgesia by Alleviating Inflammatory Factors

The pain-relieving effect of acupuncture may be due to the acupuncture-induced reduction of a variety of pain-related substances released by glial cells such as the proinflammatory cytokines, tumor necrosis factor α, interleukin-1β, interleukin-6, and prostaglandins such as prostaglandins E2.⁴⁹

A study showed that EA relieved facial and hind paw mechanical hyperalgesia in a rat model of migraine by alleviating inflammatory factors. The electrical stimulation of acupoints increased the number of mast cells and macrophages and the serum levels of inflammatory factors. EA at GB20 and GB20/34 significantly decreased the number of mast cells and macrophages and the serum levels of inflammatory factors.⁵⁰

Acupuncture-Induced Analgesia Through Orexin-Endocannabinoid in the Periaqueductal Gray

A study reported that 2 Hz EA on the PC6 (Neiguan) acupoint of mice could inhibit pain responses through releasing an endogenous neuropeptide (orexin) from the hypothalamus through an endocannabinoid (an endogenous lipid functioning like chemicals from cannabis) that reduces the inhibitory (GABAergic) control in a midbrain pain control region (the periaqueductal gray).⁵¹

Other Mechanisms Involved in Acupuncture's Analgesic Effect

A previous study found that adenosine, a neuromodulator with antinociceptive properties, was released during acupuncture in mice and that its antinociceptive actions required adenosine A1 receptor expression.⁵² Along the same line, a study found that injection of prostatic acid phosphatase into the V40 (Weizhong) acupoint had an analgesic effect, which lasted up to 6 days after a single injection.⁵³

Remarkably, a very recent study discovered that EA drives sympathetic pathways in somatotopy- and intensity-dependent manners. Specifically, whereas low-intensity EA at hindlimb regions drives the vagal-adrenal axis, producing anti-inflammatory effects that depend on Neuropeptide Y positive (NPY+) adrenal chromaffin cells, high-intensity EA at the abdomen activates NPY+ splenic noradrenergic neurons via the spinal-sympathetic axis. This finding is significant since it could form a road map for optimizing stimulation parameters to improve the efficacy and safety of acupuncture therapy.⁵⁴

Discussion

There are many studies in laboratory animals and humans in the field of acupuncture and alcohol addiction. These research activities have contributed to the significant improvement in determining the basic mechanisms of acupuncture in treating pain, including those in alcoholics. Although many studies have been conducted on mechanisms of the analgesic effect of acupuncture, studies of acupuncture's effect on pain in alcoholics are limited. Pain hypersensitivity during withdrawal from chronic excessive alcohol drinking plays a significant role in relapse drinking and event compulsive alcohol drinking. It is a crucial factor to elucidate the biological mechanism of alcohol addiction. Dysregulation of the brain reward system and activation of LHb, the “antireward” center, is believed to contribute significantly to the relapse drinking seen in alcoholics.

Conclusions

Studies provide strong evidence that acupuncture reduces withdrawal-induced negative emotional state and relapse to drug-seeking behavior by reducing hyperalgesia via the inhibition of the “antireward” system and thus the activation of the mesolimbic dopamine system. Although it is well established that acupuncture could reduce pain via the opioid-dependent mechanism, recent studies uncovered many other mechanisms that also contribute to its analgesia effect. Although recent studies have advanced much of our knowledge on the mechanisms underlying the therapeutic effects of acupuncture on drugs of abuse and alcoholism, our understanding of the mechanisms of acupuncture is far from complete. A better understanding of acupuncture's role may lead to the development of successful therapeutic intervention in treating the pain associated with drug addiction.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was made possible by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), Grant Nos. AA021657 and AA022292, and a grant from the New Jersey Health Foundation.