Chronic intermittent ethanol produces nociception through endocannabinoid-independent mechanisms in mice.

Alcohol use disorder (AUD) affects millions of people and represents a significant health and economic burden. Pain is a frequently under-treated aspect of hyperkatifeia during alcohol withdrawal, yet to date no drugs have received FDA approval for the treatment of this indication in AUD patients. This study aims to evaluate the potential of targeting bioactive lipid signaling pathways as a therapeutic approach for treating alcohol withdrawal-related pain hypersensitivity. We utilized a chronic intermittent ethanol (CIE) vapor exposure model in C57BL/6J mice of both sexes to establish alcohol dependence and demonstrated that CIE produced robust tactile allodynia and thermal hyperalgesia during withdrawal that was independent of prior blood alcohol levels. Next, we evaluated four drugs for their efficacy in reversing tactile allodynia during abstinence from CIE using a cross-over treatment design that included FDA-approved naltrexone as well as commercially available inhibitors targeting the inflammatory lipid signaling enzymes fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and 15-Lipoxygenase (LOX). None of these compounds produced significant therapeutic benefit in reversing established CIE-induced tactile allodynia, despite attenuating pain-like behaviors at these doses in other chronic pain models. Additionally, we assessed plasma endocannabinoid levels in both sexes during withdrawal. We found that there was an inherent sex difference in the endogenous anti-inflammatory endocannabinoid tone in naive mice and that CIE treatment affected endocannabinoids levels in female mice only. These findings underscore the need to better understand the underlying causes of AUD-induced allodynia and to develop novel therapeutic approaches to mitigate pain hypersensitivity in AUD patients.