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（AUDs）表现为个人、环境、 以及酒精本身，并且与疼痛障碍密切相关。除了众所周知的止痛药和 酒精中毒的麻醉作用，酒精戒断与痛觉过敏状态有关， 导致AUD-疼痛合并症患者复发。在这里，我们将测试的临床前疗效 增强内源性大麻素（eCB）用于减轻酒精戒断相关的痛觉过敏状态 并确定这些影响的潜在神经生物学机制。eCB增强和 大麻制品具有镇痛作用。我们的初步数据表明， 增强eCB信号传导，特别是eCB配体2-花生四烯酰甘油（2-AG），发挥可靠的抗 小鼠模型中的痛觉过敏效应，而2-AG水平的耗尽会导致痛觉过敏状态 与酒精戒断有关根据这些数据，我们将严格和全面地测试全球 假设2-AG水平的药理学增加将减轻与以下相关的痛觉过敏状态： 酒精戒断通过CB 1和CB 2大麻素受体的作用。我们还将检验以下假设： 内源性2-AG起到抵消戒断相关痛觉过敏状态的生理作用。我们将 接下来测试2-AG调节杏仁核-前额叶皮层（PFC）-导水管周围灰质（PAG）的假设。 神经回路我们将使用光遗传学、逆行追踪和离体电生理学来验证这一假设 2-AG信号抑制杏仁核介导的PAG投射PFC神经元的抑制。我们假设 2-AG信号在酒精戒断过程中通过抑制神经递质传递发挥镇痛作用 优先作用于PFC GABA神经元，从而增加对PAG投射PFC的兴奋/抑制比 神经元，这有助于下行疼痛调制。最后，我们将使用PAG的体内钙成像- 投射PFC神经元，以检验有害的机械刺激诱导这些神经元活动的假设。 神经元在酒精戒断中减少，并通过药理学2-AG增加而正常化， 这些神经元的活性是在酒精戒断期间增加2-AG的镇痛作用所必需的。 这些研究的完成可以为2-AG增加治疗AUD提供临床前验证。 疼痛共病，并提供新的机制洞察2-AG信号如何调节下行疼痛 生理条件下和酒精戒断期间的回路。