Miliano Cristina, Dong Yuyang, Proffit McKenzie, Cabanas Natalia Corvalan, Natividad Luis A, Buczynski Matthew W, Gregus Ann M
School of Neuroscience, Virginia Polytechnic and State University, 970 Washington Street SW, Blacksburg, VA, 24061, USA.
College of Pharmacy, Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, TX, USA.
Neuropharmacology. 2025 Oct 1;277:110502. doi: 10.1016/j.neuropharm.2025.110502. Epub 2025 May 11.
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.
酒精使用障碍（AUD）影响着数百万人，是一项重大的健康和经济负担。疼痛是酒精戒断期间痛觉过敏中一个经常未得到充分治疗的方面，但迄今为止，尚无药物获得美国食品药品监督管理局（FDA）批准用于治疗AUD患者的这一适应症。本研究旨在评估靶向生物活性脂质信号通路作为治疗酒精戒断相关疼痛超敏反应的治疗方法的潜力。我们利用慢性间歇性乙醇（CIE）蒸汽暴露模型，在雌雄C57BL/6J小鼠中建立酒精依赖，并证明CIE在戒断期间产生了强烈的触觉异常性疼痛和热痛觉过敏，这与先前的血液酒精水平无关。接下来，我们采用交叉治疗设计，评估了四种药物在逆转CIE戒断期间触觉异常性疼痛方面的疗效，该设计包括FDA批准的纳曲酮以及针对炎症脂质信号酶脂肪酸酰胺水解酶（FAAH）、单酰甘油脂肪酶（MAGL）和15-脂氧合酶（LOX）的市售抑制剂。尽管这些化合物在其他慢性疼痛模型中以这些剂量减轻了疼痛样行为，但没有一种化合物在逆转已建立的CIE诱导的触觉异常性疼痛方面产生显著的治疗益处。此外，我们评估了戒断期间雌雄小鼠的血浆内源性大麻素水平。我们发现，在未接触过酒精的小鼠中，内源性抗炎内源性大麻素张力存在固有的性别差异，并且CIE治疗仅影响雌性小鼠的内源性大麻素水平。这些发现强调了需要更好地理解AUD诱导异常性疼痛的潜在原因，并开发新的治疗方法来减轻AUD患者的疼痛超敏反应。
