Regulation of Pain by Alcohol and Endocannabinoids in the Basolateral Amygdala

摘要 慢性疼痛影响着大约1亿美国人，预计这一数字将在未来几年内增加。 几十年慢性疼痛代表了一种消极的情感状态， 娱乐性、有限摄入酒精依赖和过量饮酒。酒精会产生 25%的慢性疼痛患者和79%的高风险饮酒者使用酒精， 管理他们的痛苦。我们已经表明，急性酒精管理减弱增加疼痛敏感性（或 在我们的慢性炎性疼痛的啮齿动物模型中，酒精的镇痛作用可能会改变 在慢性疼痛的过程中。然而，在神经生物学方面的知识存在差距。 酒精在慢性疼痛中的镇痛作用机制。基底外侧 杏仁核（BLA）在各种疼痛过程中起着重要作用，包括疼痛的慢性化和疼痛的发生。 调节疼痛相关的负面情绪。慢性疼痛增加BLA自发和诱发活动 和cFos mRNA表达，我们的初步数据表明，酒精依赖和戒断 由于BLA活性的类似增加而引起疼痛敏感性增加的状态。内源性大麻素 系统（eCB）是众所周知的介导镇痛，我们已经表明，酒精戒断引起的疼痛， 回避行为与BLA内eCB张力的潜在降低相关。主要研究 目前的建议的目的是研究BLA激活和内源性大麻素信号传导在 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BLA中间神经元的背景下，慢性炎症疼痛和激活 这些神经元是酒精镇痛作用所必需的; 2）急性酒精会增加BLA 内源性大麻素和内源性大麻素分解代谢酶单酰基甘油脂酶的抑制 （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。 除了填补了关于慢性脑梗死与脑梗死之间关系的神经生物学知识的空白外， 疼痛和酒精，这项建议将提供一个有前途的未来生物医学科学博士与重要的研究 培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.