Regulation of Pain by Alcohol and Endocannabinoids in the Basolateral Amygdala

酒精和内源性大麻素对基底外侧杏仁核疼痛的调节

• 批准号: 10292427
• 负责人: Jessica Cucinello-Ragland
• 金额: $ 3.79万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2023-08-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292427
• 关键词: 2-arachidonylglycerol; 2-arachidonylglycerol signaling; Absence of pain sensation; Acute; Adjuvant; Affect; Affective; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; American; Amygdaloid structure; Analgesics; Animals; Area; Attenuated; Behavior; Brain region; Cells; Chronic inflammatory pain; Complex; Conflict (Psychology); Data; Development; Diabetes Mellitus; Doctor of Philosophy; Dose; Endocannabinoids; Enzymes; Fellowship; Female; Future; Hares; Heart Diseases; Human; Immunohistochemistry; Individual; Intake; Interneurons; Knowledge; Malignant Neoplasms; Measures; Mechanics; Mediating; Mediator of activation protein; Medical; Modeling; Monoacylglycerol Lipases; Motivation; Negative Reinforcements; Neurobiology; Neurons; Outcome; Pain; Pain Research; Pattern; Pharmacology; Phosphorylation; Play; Population; Process; Productivity; Property; Pyramidal Cells; Rattus; Regulation; Reporting; Research; Research Training; Rodent Model; Role; Science; Scientist; Signal Transduction; Site; Stimulus; System; Testing; Time; Training; Western Blotting; Work; alcohol effect; alcohol research; alcohol risk; alcohol use disorder; allodynia; avoidance behavior; chronic pain; chronic pain patient; cost; driving force; early onset; emotion regulation; endocannabinoid signaling; endogenous cannabinoid system; high risk; inflammatory pain; interest; lipoprotein lipase; mRNA Expression; male; negative affect; neuroadaptation; neurobiological mechanism; neurotransmission; pain chronification; pain sensitivity; protein expression; response; synthetic enzyme

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.

抽象的 慢性疼痛会影响约1亿美国人，这一预计将在下一件事中增加 几十年。慢性疼痛代表一个负面的情感状态，促进了从 娱乐性，有限的酒精依赖摄入量和饮酒过量。急性酒精会产生 人类的镇痛和25％的慢性疼痛患者和79％的高风险酒精饮用者使用酒精 管理他们的痛苦。我们已经表明，急性酒精给药会减轻疼痛敏感性的提高（或 在我们的慢性炎症性疼痛模型中，异常痛，酒精的镇痛作用可能会改变 在慢性疼痛的过程中。但是，关于神经生物学的知识存在差距 在慢性疼痛的背景下，酒精造成镇痛作用的机制。基底外侧 杏仁核（BLA）在各种疼痛过程中起着重要作用，包括疼痛时间和 调节疼痛相关的负面影响。慢性疼痛会增加BLA自发性和诱发活性 和CFO MRNA表达，我们的初步数据表明酒精依赖性和退出 由于BLA活性的增加，引起疼痛敏感性增加的状态。内源性大麻素 系统（欧洲央行）以介导镇痛而闻名，我们已经表明酒精戒断疼痛 回避行为与BLA内欧洲央行的欧洲荷兰语调的潜在降低有关。主要研究 当前建议的目的是研究BLA激活和内源性大麻素信号传导的作用 急性酒精的镇痛作用。该提案中概述的研究将测试以下预测：1） 急性酒精在慢性炎症性疼痛的背景下激活BLA中间神经元 这些神经元对于酒精的镇痛作用是必需的，2）急性酒精会增加BLA 内源性大麻素和抑制内源性大麻素分解代谢酶单酰基甘油脂肪酶 （MAGL）将以类似于急性酒精给药的方式来挽救类似疼痛的行为。 除了填补有关慢性之间关系的神经生物学知识的空白 痛苦和酒精，该提案将通过重要的研究提供有希望的未来生物医学科学博士 培训成为酒精研究领域的独立科学家。