Vasopressin Signaling in Pain and Alcohol Dependence

疼痛和酒精依赖中的加压素信号传导

基本信息

批准号：
10441221
负责人：
Scott Edwards
金额：
$ 33.08万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10441221
关键词：
Abstinence Affective Alcohol dependence Alcohol withdrawal syndrome Alcohols Amygdaloid structure Animal Model Animals Area Automobile Driving Behavior Brain Brain region Chronic Clinical Dependence Ethanol Female Gene Expression Gene Expression Profiling Genetic Transcription Glucocorticoid Receptor Glucocorticoids Heavy Drinking Human Hyperalgesia Hypersensitivity Individual Investigation Link Measures Mechanics Modeling Motivation Negative Reinforcements Neuropeptides Nociception Pain Persistent pain Pharmaceutical Preparations Pharmacology Phosphoproteins Phosphorylation Property Psychological reinforcement Rattus Receptor Signaling Rodent Role Severities Sex Differences Signal Transduction Site Stress System Vasopressin Receptor Vasopressins Woman Work alcohol exposure alcohol reinforcement alcohol use disorder antagonist central pain chronic pain drinking effective therapy emotional symptom experience innovation insight male men negative emotional state neuroadaptation neurobiological mechanism novel pain reduction pain sensitivity pain symptom pre-clinical receptor response sex therapeutic target vapor

项目摘要

Project Summary ______ Alcohol use disorder (AUD) is associated with the emergence of negative emotional states that can influence the motivational properties of alcohol. Pain represents one such motivational state hypothesized to drive AUD severity (Egli, Koob, and Edwards, 2012), and this relationship is particularly concerning since there are limited treatments for either chronic pain or AUD. Ascending nociceptive circuitry and excessive alcohol exposure alters the function of central brain stress and reinforcement systems, including the central amygdala (CeA). Related neuroadaptations may underlie negative reinforcement mechanisms driven by persistent pain in the context of AUD. We have discovered the emergence of a significant mechanical and thermal nociceptive hypersensitivity (or hyperalgesia) in alcohol-dependent male rats and our current aim is to interrogate valid animal models of excessive drinking and hyperalgesia toward the elucidation of neuropharmacological mechanisms contributing to these conditions in alcohol dependence. Our previous work implicated the stress neuropeptide vasopressin in the transition to dependence in male rats via its actions on V1b receptors (V1bRs; Edwards et al., 2012). While V1bR antagonists reduce excessive drinking in rodents and facilitate abstinence in alcohol-dependent individuals (Ryan et al., 2016), additional evidence suggests that they may also reduce stress-induced hyperalgesia (Bradesi et al., 2009). Pain-related affective responses are also enhanced via vasopressin signaling through CeA V1a receptors (V1aRs, Cragg et al., 2016), although the contribution of this receptor system to excessive drinking or hyperalgesia in the context of alcohol dependence is unexplored. As two key stress-regulatory systems, vasopressin and glucocorticoid signaling may closely interact, with each system driving the other's activity in a bidirectional fashion. Elucidation of this link could be critical to understanding the efficacy of glucocorticoid receptor antagonist therapy in reducing excessive drinking in preclinical and clinical models (Vendruscolo et al., 2015). Our primary hypothesis is that blockade of either of two subclasses of central vasopressin receptors (V1bRs or V1aRs) in a key pain- and reinforcement-related brain area (CeA) will reduce both excessive drinking and hyperalgesia in alcohol-dependent animals. Our secondary hypothesis is that blockade of vasopressin V1bR signaling will reduce GR phosphorylation in the CeA of alcohol-dependent animals, while blockade of GR transcription activity will also reduce vasopressin system gene expression in the CeA. We also propose an investigation of sex as a factor in these relationships given the substantial human sex differences in alcohol withdrawal and pain. A better understanding of the central brain mechanisms of alcohol dependence-related behaviors (excessive drinking and hyperalgesia) will provide substantial insight into neurobiological mechanisms of dependence and may reveal novel treatment opportunities for AUD and persistent pain in the context of AUD.

项目概要______ 酒精使用障碍 (AUD) 与负面情绪状态的出现有关，这些情绪状态会影响酒精的激励特性。疼痛代表了一种被假设推动澳元上涨的动机状态严重性（Egli、Koob 和 Edwards，2012），这种关系尤其令人担忧，因为有限的治疗慢性疼痛或 AUD。上升的伤害性电路和过量的酒精暴露改变中枢大脑压力和强化系统的功能，包括中央杏仁核（CeA）。相关的神经适应可能是由持续疼痛驱动的负强化机制的基础。澳元的背景。我们发现出现了显着的机械和热伤害感受酒精依赖型雄性大鼠的超敏反应（或痛觉过敏），我们当前的目标是询问有效的过度饮酒和痛觉过敏的动物模型，以阐明神经药理学导致这些酒精依赖状况的机制。我们之前的工作涉及到压力神经肽加压素通过其对 V1b 受体（V1bRs；V1bRs；爱德华兹等人，2012）。 V1bR 拮抗剂可减少啮齿动物的过度饮酒并促进戒酒在酒精依赖者中（Ryan 等人，2016），其他证据表明他们也可能减少压力诱发的痛觉过敏（Bradesi 等，2009）。与疼痛相关的情感反应也通过以下方式得到增强：加压素信号通过 CeA V1a 受体（V1aRs，Cragg 等人，2016），尽管这一贡献酒精依赖背景下过度饮酒或痛觉过敏的受体系统尚未被探索。作为两个关键的应激调节系统，加压素和糖皮质激素信号传导可能密切相互作用，每个系统系统以双向方式驱动对方的活动。阐明这一联系可能至关重要了解糖皮质激素受体拮抗剂治疗在减少过度饮酒方面的功效临床前和临床模型（Vendruscolo 等人，2015）。我们的主要假设是封锁中枢加压素受体（V1bR 或 V1aR）的两个亚类在关键的疼痛和强化相关中大脑区域（CeA）将减少酒精依赖动物的过度饮酒和痛觉过敏。我们的第二个假设是，阻断加压素 V1bR 信号传导会减少 GR 磷酸化酒精依赖动物的CeA，而阻断GR转录活性也会减少加压素 CeA 中的系统基因表达。我们还建议对性别作为这些关系中的一个因素进行调查鉴于人类在酒精戒断和疼痛方面存在巨大的性别差异。更好地理解酒精依赖相关行为（过量饮酒和痛觉过敏）的中枢大脑机制将提供对依赖的神经生物学机制的深入见解，并可能揭示新的治疗方法澳元的机会和澳元背景下的持续痛苦。