Endocannabinoid signaling in the lateral habenula regulates pain and alcohol consumption

Rao Fu,Xuejun Chen,Alex Bekker,Qi Kang Zuo,Yucong Zou,Kelsey L Tam,Jiang-Hong Ye,Ying Tang,Thomas Bachmann,Ding Li,Wanhong Zuo,Zhiheng Ren,Jiayi Zheng,Wenfu Li

doi:10.1038/s41398-021-01337-3

Abstract

Hyperalgesia, which often occurs in people suffering from alcohol use disorder, may drive excessive drinking and relapse. Emerging evidence suggests that the lateral habenula (LHb) may play a significant role in this condition. Previous research suggests that endocannabinoid signaling (eCBs) is involved in drug addiction and pain, and that the LHb contains core components of the eCBs machinery. We report here our findings in rats subjected to chronic ethanol vapor exposure. We detected a substantial increase in endocannabinoid-related genes, including Mgll and Daglb mRNA levels, as well as monoacylglycerol lipase (MAGL) protein levels, as well as a decrease in Cnr1 mRNA and type-1 cannabinoid receptor (CB1R) protein levels, in the LHb of ethanol-exposed rats. Also, rats withdrawing from ethanol exposure displayed hypersensitivity to mechanical and thermal nociceptive stimuli. Conversely, intra-LHb injection of the MAGL inhibitor JZL184, the fatty acid amide hydrolase inhibitor URB597, or the CB1R agonist WIN55,212-2 produced an analgesic effect, regardless of ethanol or air exposure history, implying that alcohol exposure does not change eCB pain responses. Intra-LHb infusion of the CB1R inverse agonist rimonabant eliminated the analgesic effect of these chemicals. Rimonabant alone elicited hyperalgesia in the air-, but not ethanol-exposed animals. Moreover, intra-LHb JZL184, URB597, or WIN55,212-2 reduced ethanol consumption in both homecages and operant chambers in rats exposed to ethanol vapor but not air. These findings suggest that LHb eCBs play a pivotal role in nociception and facilitating LHb eCBs may attenuate pain in drinkers.

Highlights

Alcohol use disorders (AUD) affect 15 million Americans (Substance Abuse and Mental Health Services Administration, 2015) and are closely tied to chronic pain in humans
Chronic intermittent ethanol vapor exposure increases sensitivity to mechanical and thermal nociceptive stimuli We set up an alcohol-dependent rat model using a chronic intermittent ethanol exposure (CIE) protocol, as described[26,39]
Pharmacological corrections of the impaired lateral habenula (LHb) endocannabinoid signaling (eCBs) signaling effectively reduced pain and ethanol intake. These findings highlight the vital role of the LHb eCB system in pain associated with AUD

Summary

Introduction

Alcohol use disorders (AUD) affect 15 million Americans (Substance Abuse and Mental Health Services Administration, 2015) and are closely tied to chronic pain in humans. AUD and chronic pain share common neural circuits giving rise to the possibility that chronic pain states could significantly affect alcohol use patterns, and AUD could influence pain sensitivity[1]. Recent studies suggest that around 1 in 4 adults in chronic pain report self-medicating with alcohol, and 43–73% of people with. Various brain circuits have been implicated in AUD-. The lateral habenula (LHb) has recently emerged as an essential brain region that controls the expression of aversive behaviors, including those related to alcohol[3,4,5,6,7,8]. Work from our laboratory has shown that the LHb plays an important role in anxiety- and depression-like behaviors associated with AUD9–11, and that these aberrant behaviors are concomitant with increased activity of, as well as glutamatergic transmissions to, LHb neurons[11,12]

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