Endocannabinoid Mechanisms in the Pathophysiology of Alcohol Use Disorders

酒精使用障碍病理生理学中的内源性大麻素机制

• 批准号: 10587760
• 负责人: Sachin Patel
• 金额: $ 36万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587760
• 关键词: 2-arachidonylglycerol; Abstinence; Affect; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; Amygdaloid structure; Analgesics; Anesthetics; Anxiety; Award; Behavior; Biological Assay; Biological Models; CNR1 gene; CNR2 gene; Calcium; Cannabis; Characteristics; Data; Disinhibition; Dose; Electrophysiology (science); Endocannabinoids; Environment; Enzymes; Functional disorder; Funding; Glutamates; Hyperalgesia; Hypersensitivity; Image; Individual; Insula of Reil; Interneurons; Investigation; Label; Ligands; Link; MAGL inhibitor; Mechanical Stimulation; Mechanics; Mediating; Medical; Modeling; Monoacylglycerol Lipases; Motivation; Mus; Negative Reinforcements; Neurons; Nociceptive Stimulus; Pain; Pain Disorder; Pain Threshold; Pathway interactions; Patients; Phenotype; Physiological; Population; Preclinical Testing; Prefrontal Cortex; Prevalence; Process; Prognosis; Property; Regulation; Relapse; Role; Sensory; Signal Transduction; Synapses; System; Testing; Therapeutic; Validation; Viral; Withdrawal; alcohol abuse therapy; alcohol effect; alcohol relapse; alcohol use disorder; cannabinoid receptor; cell cortex; chronic alcohol ingestion; chronic pain; comorbidity; depressive symptoms; endocannabinoid signaling; endogenous cannabinoid system; gamma-Aminobutyric Acid; in vivo; in vivo calcium imaging; insight; lipoprotein lipase; midbrain central gray substance; mouse model; negative affect; neural circuit; neurobiological mechanism; neuromechanism; novel; novel strategies; optogenetics; pain processing; pharmacologic; pre-clinical; preclinical efficacy; prevent; sciatic nerve injury; transmission process

PROJECT SUMMARY Alcohol use disorders (AUDs) manifest from a convergence of characteristics of the individual, the environment, and the alcohol itself, and is strongly associated with pain disorders. In addition to the well-known analgesic and anesthetic effects of alcohol intoxication, alcohol withdrawal is associated with hyperalgesic states which contribute to relapse in patients with AUD-pain comorbidities. Here we will test the preclinical efficacy of endocannabinoid (eCB) augmentation for the alleviation of alcohol withdrawal-associated hyperalgesic states and determine the underlying neurobiological mechanisms subserving these effects. eCB augmentation and cannabis products are known to exert analgesic effects. Our preliminary data demonstrate that pharmacological augmentation of eCB signaling, specifically the eCB ligand 2-arachidonoylglycerol (2-AG), exerts reliable anti- hyperalgesic effects in mouse models, while depletion of 2-AG levels worsens and prolongs hyperalgesic states associated with alcohol withdrawal. Based on these data we will rigorously and comprehensively test the global hypothesis that pharmacological augmentation of 2-AG levels will alleviate hyperalgesic states associated with alcohol withdrawal via actions at CB1 and CB2 cannabinoid receptors. We will also test the hypothesis that endogenous 2-AG serves a physiological role to counteract withdrawal-associated hyperalgesic states. We will next test the hypothesis that 2-AG regulates an amygdala-prefrontal cortical (PFC)-periaqueductal gray (PAG) neural circuit. We will use optogenetics, retrograde tracing, and ex vivo electrophysiology to test the hypothesis that 2-AG signaling suppresses amygdala-mediated inhibition of PAG-projecting PFC neurons. We hypothesize that 2-AG signaling exerts analgesic actions in alcohol withdrawal via inhibition of glutamatergic transmission preferentially onto PFC GABA neurons thus increasing the excitation/inhibition ratio onto PAG-projecting PFC neurons, which contribute to descending pain modulation. Lastly, we will use in vivo calcium imaging of PAG- projecting PFC neurons to test the hypothesis that noxious mechanical stimulation-induced activity of these neurons is reduced in alcohol withdrawal and normalized by pharmacological 2-AG augmentation, and that activity of these neurons is required for the analgesic effects of 2-AG augmentation during alcohol withdrawal. Completion of these studies could provide preclinical validation for 2-AG augmentation in the treatment of AUD- pain comorbidity and provide novel mechanistic insight into how 2-AG signaling regulates descending pain circuits under physiological conditions and during alcohol withdrawal.

项目摘要 酒精使用障碍（AUD）表现出来自个人，环境的特征的收敛性 酒精本身，与疼痛障碍密切相关。除了众所周知的镇痛药和 酒精中毒的麻醉作用，戒酒与高过敏状态有关 有助于呼吸蛋白酶合并症患者的复发。在这里，我们将测试 内源性大麻素（欧洲央行）增强，以减轻酒精戒断相关的痛觉过敏状态 并确定潜在的神经生物学机制，这些机制可以增强这些作用。欧洲欧洲央行和 已知大麻产物会发挥镇痛作用。我们的初步数据表明药理 欧洲央行信号传导的增强，特别是欧洲央行配体2-芳基烯丙基甘油（2-AG），发挥可靠的抗 - 小鼠模型中的高温作用，而2AG水平的耗竭会恶化并延长痛风状态 与戒酒有关。基于这些数据，我们将严格，全面地测试全局 假设2AG水平的药理学增强将减轻与 通过CB1和CB2大麻素受体的作用提取酒精。我们还将检验以下假设 内源性2-AG发挥了生理作用，可以抵消与戒断相关的痛觉过敏状态。我们将 接下来检验2-AG调节杏仁核皮质（PFC） - 透明灰色（PAG）的假设 神经电路。我们将使用光遗传学，逆行跟踪和离体电生理学来检验假设 2-AG信号传导抑制了杏仁核介导的PAG投射PFC神经元的抑制作用。我们假设 2 ag信号传导通过抑制谷氨酸能传播在戒酒中发挥镇痛作用 优先在PFC GABA神经元上增加了激发/抑制比在PAG-PAG Projection PFC上 神经元，会导致疼痛下降。最后，我们将使用PAG的体内钙成像 投射PFC神经元来检验以下假设： 在戒酒中降低神经元，并通过药理学2-AG增强进行标准化，并且 这些神经元的活性对于戒酒期间2-AG增强的镇痛作用是必需的。 这些研究的完成可以为2 AG增强提供临床前验证 疼痛合并症，并提供有关2-AG信号如何调节下降疼痛的新机械洞察力 在生理条件下和戒酒期间的电路。