Vasopressin Signaling in Pain and Alcohol Dependence

项目概要_ 酒精使用障碍（AUD）与负面情绪状态的出现有关， 酒精的激励特性疼痛代表了一种假设驱动AUD的动机状态 严重性（Egli，Koob和Edwards，2012），这种关系特别令人担忧，因为存在有限的 治疗慢性疼痛或AUD。上行伤害性感受回路与过量酒精暴露 改变了中央大脑应激和强化系统的功能，包括中央杏仁核（CeA）。 相关的神经适应可能是由持续性疼痛驱动的负强化机制的基础。 澳元的背景。我们已经发现了一个重要的机械和热伤害感受的出现， 超敏反应（或痛觉过敏）在酒精依赖的雄性大鼠，我们目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 酒精依赖的机制。我们之前的研究表明 神经肽加压素通过作用于V1 b受体（V1 bRs; Edwards等人，2012年）。虽然V1 bR拮抗剂可减少啮齿类动物的过度饮酒并促进禁欲 在酒精依赖个体中（Ryan等人，2016年），额外的证据表明，它们也可能减少 应激诱导的痛觉过敏（Bradesi等，2009年）。疼痛相关的情感反应也会通过 通过CeA V1 a受体的加压素信号传导（V1 aRs，Cragg等，2016年），尽管这一贡献 在酒精依赖的背景下，过度饮酒或痛觉过敏的受体系统尚未探索。作为 两个关键的压力调节系统，加压素和糖皮质激素信号可能密切相互作用， 以双向方式驱动另一个系统的活动。阐明这一联系可能是至关重要的， 了解糖皮质激素受体拮抗剂治疗在减少过度饮酒方面的疗效， 临床前和临床模型（Vendruscolo等人，2015年）。我们的主要假设是， 中枢加压素受体（V1 bRs或V1 aRs）的两个亚类在一个关键的疼痛和疼痛相关的 脑区（CeA）将减少酒精依赖动物的过度饮酒和痛觉过敏。我们 第二个假设是，血管加压素V1 bR信号传导的阻断将减少GR磷酸化， 酒精依赖动物的CeA，同时阻断GR的转录活性也会降低后叶加压素 CeA中的系统基因表达。我们还建议调查性作为这些关系的一个因素 鉴于人类在戒酒和疼痛方面的巨大性别差异。更好地理解 酒精依赖相关行为（过量饮酒和痛觉过敏）的中枢脑机制将 提供了对依赖的神经生物学机制的实质性了解，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。

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.