Regulation of Pain by Alcohol and Endocannabinoids in the Basolateral Amygdala

摘要 慢性疼痛影响了大约1亿美国人，这个数字预计在接下来的一年里还会增加 几十年了。慢性疼痛代表了一种消极的情感状态，它促进了从 娱乐，对酒精依赖和过度饮酒的摄入量有限。尖锐地说，酒精会产生 人类的止痛，25%的慢性疼痛患者和79%的高危饮酒者使用酒精来 控制他们的痛苦。我们已经证明，急性酒精摄入可以减轻疼痛敏感度的增加(或 在我们的慢性炎症性疼痛的啮齿动物模型中)，酒精的止痛作用可能会改变 在慢性疼痛的过程中。然而，关于神经生物学方面的知识存在差距。 酒精在慢性疼痛背景下止痛作用的潜在机制。基底外侧 杏仁核(BLA)在多种疼痛过程中发挥重要作用，包括疼痛时代化和 疼痛相关负性情绪的调节。慢性疼痛增加血乳酸自发和诱发活动 和CFOS mRNA的表达，我们的初步数据表明，酒精依赖和戒断 由于BLA活性的类似增加而导致疼痛敏感性增加的状态。内源性大麻素 系统(ECB)是众所周知的中介止痛，我们已经证明，酒精戒断引起的疼痛 回避行为与欧洲央行在BLA内的语气下降有关。主要研究内容 本研究的目的是研究BLA激活和内源性大麻素信号转导在脑出血中的作用。 急性酒精的镇痛作用。本提案中概述的研究将检验以下预测：1) 急性酒精激活慢性炎症性疼痛背景下的BLA中间神经元 这些神经元对酒精的止痛作用是必需的，2)急性酒精会增加血乳酸 内源性大麻素及其对内源性大麻素分解代谢酶单甘油脂肪酶抑制作用 (MAGL)将以类似于急性酒精给药的方式挽救疼痛样行为的增加。 除了填补关于慢性疾病之间关系的神经生物学方面的知识空白 疼痛和酒精，这项提议将为未来的生物医学科学博士提供重要的研究 受训成为酒精研究领域的独立科学家。

Abstract Chronic pain affects approximately 100 million Americans, a number that is projected to increase over the next several decades. Chronic pain represents a negative affective state that promotes the transition from recreational, limited intake to alcohol dependence and excessive alcohol drinking. Acutely, alcohol produces analgesia in humans, and 25% of chronic pain patients and 79% of high-risk alcohol drinkers use alcohol to manage their pain. We have shown that acute alcohol administration attenuates increased pain sensitivity (or allodynia) in our rodent model of chronic inflammatory pain, and that the analgesic effects of alcohol may shift over the course of chronic pain. However, there is a gap in knowledge regarding the neurobiological mechanisms underlying the analgesic effects of alcohol in the context of chronic pain. The basolateral amygdala (BLA) plays an important role in various pain processes, including pain chronification and the regulation of pain-associated negative affect. Chronic pain increases BLA spontaneous and evoked activity and cFos mRNA expression, and our preliminary data suggest that alcohol dependence and withdrawal induces a state of increased pain sensitivity due to a similar increase in BLA activity. The endocannabinoid system (eCB) is well known for mediating analgesia, and we have shown that alcohol withdrawal-induced pain avoidance behavior is associated with a potential decrease in eCB tone within the BLA. The main research objective of the current proposal is to investigate the role of BLA activation and endocannabinoid signaling in the analgesic effects of acute alcohol. The studies outlined in this proposal will test the predictions that: 1) acute alcohol activates BLA interneurons in the context of chronic inflammatory pain and that activation of these neurons are necessary for the analgesic effects of alcohol, and 2) that acute alcohol will increase BLA endocannabinoids and that inhibition of the endocannabinoid catabolic enzyme monoacylglycerol lipase (MAGL) will rescue increases in pain-like behavior in a manner similar to that of acute alcohol administration. In addition to filling a gap in knowledge regarding the neurobiology underlying the relationship between chronic pain and alcohol, this proposal will provide a promising future biomedical science PhD with vital research training to become an independent scientist in the field of alcohol research.