2-Arachodonoylglycerol-mediated endocannabinoid signaling modulates mechanical hypersensitivity associated with alcohol withdrawal in mice

Alcohol use disorder (AUDs) commonly co-occurs in patients with chronic pain, and a major barrier to achieving abstinence and preventing relapse is the emergence of hyperalgesia during alcohol withdrawal. Elucidating novel therapeutic approaches to target hyperalgesia associated with alcohol withdrawal could have important implications for the treatment of AUD. Here we examined the role of 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid (eCB) signaling in the regulation of hyperalgesia associated with alcohol withdrawal in mice and tested the hypothesis that pharmacological augmentation of 2-AG signaling could reduce hyperalgesia during withdrawal. After 72 hours of withdrawal from a continuous access two-bottle choice drinking paradigm, male and female mice exhibited increased mechanical but not thermal hypersensitivity, which normalized by 7 days. This effect was reversed by pretreatment with the monoacylglycerol lipase (MAGL) inhibitor JZL184, which elevates levels of 2-AG. The effects of JZL184 were prevented by coadministration of either a CB1 or CB2 antagonist. Inhibition of the 2-AG synthetic enzyme diacylglycerol lipase (DAGL) with DO34 exacerbated mechanical hypersensitivity during alcohol withdrawal, causing an earlier onset and persistent hypersensitivity even one week into withdrawal. Our findings demonstrate the critical role of 2-AG signaling in the bidirectional regulation of mechanical sensitivity during alcohol withdrawal, with enhancement of 2-AG levels reducing sensitivity, and inhibition of 2-AG synthesis exacerbating sensitivity. These data suggest 2-AG augmentation could represent a novel approach to the treatment of alcohol withdrawal-associated hyperalgesia and AUD in patients with comorbid pain disorders.