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：
9761937
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761937
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 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.

项目摘要______ 酒精使用障碍（AUD）与可能影响的负面情绪状态的出现有关酒精的动机特性。痛苦代表这样一个动机状态，假设驱动AUD 严重性（Egli，Koob和Edwards，2012年），这种关系尤其令人担忧，因为有限慢性疼痛或aud的治疗方法。上升伤害感电路和过多的酒精暴露改变了包括中央杏仁核（CEA）在内的中央大脑应力和增强系统的功能。相关的神经适应可能是由负面强化机制的基础澳元的上下文。我们发现出现了重要的机械和热伤害性酒精依赖性雄性大鼠的高敏性（或痛觉过敏），我们目前的目的是询问有效过度饮酒和痛苦的动物模型阐明神经药物在酒精依赖中导致这些条件的机制。我们以前的工作暗示了压力神经肽加压素在雄性大鼠对V1b受体的作用（V1BRS； Edwards等，2012）。而v1br拮抗剂减少了啮齿动物的过量饮酒并促进戒酒在依赖酒精的个体中（Ryan等，2016），其他证据表明，它们也可能减少压力诱导的痛觉过敏（Bradesi等，2009）。与疼痛有关的情感反应也通过加压素通过CEA V1A受体信号传导（V1ARS，Cragg等，2016），尽管该受体的贡献在酒精依赖背景下，受体系统会导致过度饮酒或痛觉过敏。作为两个关键的应力调节系统，加压素和糖皮质激素信号传导可能与每种信号相互作用系统以双向方式推动对方的活动。阐明此链接可能至关重要了解糖皮质激素受体拮抗剂疗法在降低过量饮酒方面的功效临床前和临床模型（Vendruscolo等，2015）。我们的主要假设是对任何一个的封锁关键疼痛和增强相关的中央加压素受体（V1BRS或V1AR）的两个子类大脑区域（CEA）将减少依赖酒精依赖动物的过度饮酒和超痛性。我们的次要假设是加压素V1BR信号的阻断将减少GR磷酸化酒精依赖性动物的CEA，而GR转录活性的阻断也会减少加压素 CEA中的系统基因表达。我们还提出了对性别的调查作为这些关系的一个因素鉴于人类戒断和疼痛的人性性别差异很大。更好地理解酒精依赖相关行为的中央脑机制（过度饮酒和痛苦）将提供对依赖神经生物学机制的大量见解，并可能揭示新的治疗方法在AUD背景下，AUD和持续疼痛的机会。