Rodent model of alcohol related hyperalgesia

酒精相关痛觉过敏啮齿动物模型

• 批准号: 10189448
• 负责人: Mary Magdalen Heinricher
• 金额: $ 34.65万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189448
• 关键词: Acute; Address; Affect; Agreement; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; American; Animals; Anterior; Anxiety; Area; Behavior; Behavior Therapy; Brain region; Chemicals; Cholecystokinin; Chronic; Cues; Empathy; Exhibits; FOS gene; Family member; Female; Glutamates; Goals; Heavy Drinking; House mice; Hyperalgesia; Hypersensitivity; Hypothalamic structure; Insula of Reil; Intervention Studies; Laboratories; Link; Measures; Mechanics; Mediating; Mental Depression; Mus; Mutant Strains Mice; Neurons; Neuropeptides; Neurosciences; Nociception; Pain; Pathology; Patients; Pharmacotherapy; Play; Population; Procedures; Regulation; Reporting; Research; Rodent Model; Role; Self Administration; Severities; Spouses; Testing; Thermal Hyperalgesias; Time; Withdrawal; alcohol abuse therapy; biological adaptation to stress; chronic pain; chronic pain patient; chronic painful condition; designer receptors exclusively activated by designer drugs; drinking; drinking behavior; experimental study; hypothalamic-pituitary-adrenal axis; male; negative affect; neuromechanism; novel; pain perception; pain relief; pain sensitivity; prairie vole; preclinical study; problem drinker; social; therapy development; transcription factor; treatment trial

Project Summary Over a hundred million of Americans suffer from chronic pain and over ten million of Americans suffer from alcohol abuse or dependence. There is a bidirectional relationship between chronic pain and alcohol dependence. Thus, alcohol dependence is a major predictor of severity of chronic pain, and people with chronic pain conditions are more likely to use alcohol for pain relief. Unfortunately, a mechanistic understanding of alcohol-related pain sensitivity is lacking. Our studies have identified increased pain sensitivity in mice during withdrawal from voluntary alcohol self-administration. Consumption of alcohol in these mice reversed mechanical hypersensitivity produced by alcohol withdrawal. The increased pain sensitivity in mice undergoing withdrawal is consistent with increased pain in alcohol-dependent patients. In addition, we found increased pain sensitivity in control “bystander” mice housed in the same room as mice undergoing alcohol withdrawal. The social transfer of hyperalgesia from mice undergoing withdrawal to the bystander mice involved olfactory cues. Such social transfer of hyperalgesia could affect "co-dependent" family members of alcoholic patients. Immunohistochemical analysis revealed differential activation of dorsomedial hypothalamus, anterior cingulate and anterior insular cortex in these animals. We hypothesize that the identified brain regions are differentially involved in alcohol withdrawal-induced hyperalgesia and socially-transferred hyperalgesia. The goal of this proposal is to address this hypothesis and further characterize the phenomena of alcohol withdrawal- and social transfer-induced hyperalgesia. This goal will be achieved in three Specific Aims: Aim 1 will further characterize the phenomenon of hyperalgesia in alcohol withdrawing and bystander mice by examining whether the observed thermal hyperalgesia is exaggerated in female bystander mice, involves negative affective states, anxiety or stress responses, or coexists with depression-like behaviors. Aim 2 will test whether alcohol-induced activation of neuronal populations within dorsomedial hypothalamus is necessary and sufficient for regulation of pain sensitivity and alcohol drinking behavior in mice. Aim 3 will test whether alcohol withdrawal and social transfer-induced activation of neurons of anterior cingulate and/or insula are necessary and sufficient for regulation of pain sensitivity.

项目概要 超过一亿美国人患有慢性疼痛，超过一千万美国人患有慢性疼痛 酗酒或依赖。慢性疼痛和酒精之间存在双向关系 依赖性。因此，酒精依赖是慢性疼痛严重程度的主要预测因素，患有慢性疼痛的人 慢性疼痛更有可能使用酒精来缓解疼痛。不幸的是，机械论 缺乏对酒精相关疼痛敏感性的了解。我们的研究发现疼痛加剧 小鼠在退出自愿酒精自我给药期间的敏感性。饮酒这些 小鼠逆转了因戒酒而产生的机械超敏反应。疼痛敏感性增加 小鼠戒断反应与酒精依赖患者的疼痛加剧一致。此外，我们 发现与接受治疗的小鼠住在同一房间的对照“旁观者”小鼠的疼痛敏感性增加 酒精戒断。痛觉过敏从戒断小鼠到旁观者小鼠的社会转移 涉及嗅觉线索。这种痛觉过敏的社会转移可能会影响“相互依赖”的家庭成员 酗酒者。免疫组织化学分析揭示了下丘脑背内侧的差异激活， 这些动物的前扣带皮层和前岛叶皮质。我们假设已识别的大脑区域 不同程度地参与酒精戒断引起的痛觉过敏和社会转移性痛觉过敏。 该提案的目标是解决这一假设并进一步描述酒精现象 戒断和社会转移引起的痛觉过敏。这一目标将通过三个具体目标来实现： 目标 1 将进一步表征酒精戒断小鼠和旁观者小鼠的痛觉过敏现象 检查雌性旁观者小鼠中观察到的热痛觉过敏是否被夸大，涉及 负面情感状态、焦虑或压力反应，或与抑郁样行为共存。目标2将 测试酒精诱导下丘脑背内侧神经元群的激活是否必要 并足以调节小鼠的疼痛敏感性和饮酒行为。目标 3 将测试是否 酒精戒断和社会转移引起的前扣带回和/或岛叶神经元的激活是 对于调节疼痛敏感性是必要且充分的。