Vasopressin Signaling in Pain and Alcohol Dependence

项目摘要_ 酒精使用障碍(AUD)与负面情绪状态的出现有关，这些情绪状态可以影响 酒精的激励作用。疼痛代表了一种这样的动机状态，假设它会推动AUD 严重性(Egli，Koob和Edwards，2012)，这种关系尤其令人担忧，因为 治疗慢性疼痛或澳门氏症。上行伤害性神经回路与过量酒精暴露 改变中枢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持续性疼痛驱动的负性强化机制的基础 澳元的背景。我们已经发现了一种重要的机械和热伤害感受器的出现 酒精依赖雄性大鼠的过敏(或痛觉过敏)，我们目前的目标是询问有效的 过度饮酒和痛敏动物模型对神经药理作用的阐明 酒精依赖导致这些情况的机制。我们之前的工作证明了压力 神经肽加压素通过作用于V1b受体(V1bRs； Edwards等人，2012年)。而V1bR拮抗剂可减少啮齿类动物的过量饮酒，促进戒酒 在酒精依赖者中(Ryan等人，2016)，更多的证据表明，它们也可能减少 应激引起的痛觉过敏(Bradesi等人，2009年)。疼痛相关的情感反应也会通过 通过CEA V1a受体的加压素信号(V1aRs，Cragg等人，2016)，尽管这一贡献 在酒精依赖的背景下，过量饮酒或痛觉过敏的受体系统尚未被探索。AS 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 以双向方式驱动对方活动的系统。阐明这一联系可能对 糖皮质激素受体拮抗剂治疗在减少饮酒中的作用 临床前和临床模型(Vendruscolo等人，2015年)。我们的主要假设是，对其中任何一个的封锁 中枢加压素受体(V1bRs或V1aRs)的两个亚类在关键的疼痛和强化相关 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信号将减少GR的磷酸化。 酒精依赖动物的CEA，而阻断GR转录活性也会减少加压素 CEA中系统基因的表达。我们还建议将性作为这些关系中的一个因素进行调查 考虑到人类在戒酒和疼痛方面的显著性别差异。更好地理解 酒精依赖相关行为(酗酒和痛觉过敏)的中枢大脑机制将 提供对依赖的神经生物学机制的实质性洞察，并可能揭示新的治疗方法 AUD的机会和AUD背景下的持续性疼痛。

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.