Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA; Department of Neuroscience, Psychology, Drug Research, and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Pharmacol Res. 2024 Nov;209:107462. doi: 10.1016/j.phrs.2024.107462. Epub 2024 Oct 11.
Epidemiological data indicate a strong association between alcohol use disorder (AUD) and neuropathic pain. Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats exhibit a high preference for alcohol compared with their background strain (Wistar rats), but their sensitivity to mechanical allodynia after chronic alcohol exposure is unknown. The present study compared the development of mechanical allodynia between "low, non-pathological drinker" Wistar rats and "high drinker" msP rats using the two-bottle choice (2BC) free-access procedure. Several studies reported the involvement of endocannabinoids (eCBs) in modulating mechanical allodynia, but there are no data on their role in alcohol-related allodynia. Thus, the present study assessed eCBs and their related lipid species in lumbar dorsal root ganglia (DRG) and correlated them with mechanical allodynia in our model. We found that male and female msP rats developed persistent mechanical allodynia during protracted abstinence from alcohol, presenting no sign of recovery, as opposed to Wistar rats. This effect directly correlated with their total alcohol intake. Notably, we found a correlation between lower lumbar DRG 2-arachidonoylglycerol (2-AG) levels and the development of higher mechanical allodynia during abstinence in msP rats of both sexes but not in Wistar rats. Moreover, alcohol-exposed and abstinent msP and Wistar females but not males exhibited significant alterations of thromboxane B2 and prostaglandin E2/prostaglandin D2 compared with naive rats. These findings demonstrate that DRG 2-AG metabolism is altered in msP rats during prolonged abstinence and represents a potentially interesting pharmacological target for the treatment of mechanical allodynia during alcohol abstinence.
流行病学数据表明，酒精使用障碍（AUD）与神经病理性疼痛之间存在很强的关联。遗传选择的 Marchigian Sardinian 酒精偏好（msP）大鼠与它们的背景品系（Wistar 大鼠）相比，表现出对酒精的高度偏好，但它们在慢性酒精暴露后对机械性痛觉过敏的敏感性尚不清楚。本研究使用双瓶选择（2BC）自由接触程序比较了“低、非病理性饮酒”Wistar 大鼠和“高饮酒”msP 大鼠之间机械性痛觉过敏的发展。有几项研究报道了内源性大麻素（eCBs）在调节机械性痛觉过敏中的作用，但没有关于它们在与酒精相关的痛觉过敏中的作用的数据。因此，本研究评估了 eCBs 及其相关脂质种类在腰椎背根神经节（DRG）中的作用，并将其与我们模型中的机械性痛觉过敏相关联。我们发现，雄性和雌性 msP 大鼠在长时间戒酒后持续出现机械性痛觉过敏，没有恢复的迹象，而 Wistar 大鼠则没有。这种效应与它们的总酒精摄入量直接相关。值得注意的是，我们发现，在 msP 大鼠的下腰椎 DRG 中，2-花生四烯酸甘油（2-AG）水平与戒断期间更高的机械性痛觉过敏的发展之间存在相关性，但在 Wistar 大鼠中则没有。此外，与未接触酒精的大鼠相比，酒精暴露和戒断的 msP 和 Wistar 雌性大鼠但不是雄性大鼠表现出血栓素 B2 和前列腺素 E2/前列腺素 D2 的显著改变。这些发现表明，在长时间戒断期间，msP 大鼠的 DRG 2-AG 代谢发生改变，这代表了治疗酒精戒断期间机械性痛觉过敏的一个潜在有趣的药理学靶点。
