Endocannabinoid signaling in the lateral habenula regulates pain and alcohol consumption

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.

Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective

“…Similarly, a recent study demonstrated that exposure to alcohol in rats decreases CB1R expression, but in contrast, increases MAGL with no change in FAAH. Interestingly, this study also found that activation of eCB signaling within the LHb is an analgesic and could reduce ethanol intake (Fu et al, 2021). Additionally, KO of MAGL can promote anxiety-and pro-depressive behaviors (Imperatore et al, 2015) providing additional evidence for a critical role of eCB modulation of neural circuits that regulate stress-related behaviors.…”

The Synaptic Interactions of Alcohol and the Endogenous Cannabinoid System

“… 147 Consistent with these findings, 12 weeks of CIE vapor reduced Cnr1 and CB 1 levels in the rat lateral habenula, while enhancing levels of the eCB-related mRNA and/or proteins, DAGL-beta, NAPE-PLD mRNA ( napepld ), and MAGL. 152 In contrast, no change in CB 1 receptor binding and mRNA levels occurred in the hippocampus, cerebral cortex, or motor and limbic structures in a chronic ethanol intake model (7% liquid diet for 15 days). 153 …”

Biomarkers of the Endocannabinoid System in Substance Use Disorders

“…Furthermore, other authors showed that chronic ethanol vapor exposure increases MGLL and DAGLB mRNA and MAGL protein levels. These changes were accompanied by a significant decrease in CNR1 mRNA and CB1R protein levels in alcohol-exposed rats [51]. The implication of CNR1 genes in alcohol intake was also evaluated in a study using the CRISP/CAS9 method.…”