Rodent model of alcohol related hyperalgesia

项目摘要 超过一亿的美国人患有慢性疼痛，超过一千万的美国人患有 酒精滥用或依赖。慢性疼痛和酒精之间存在双向关系 依赖因此，酒精依赖是慢性疼痛严重程度的主要预测因素， 慢性疼痛更可能使用酒精来缓解疼痛。不幸的是，一个机械的 缺乏对酒精相关疼痛敏感性的了解。我们的研究发现， 小鼠在自愿酒精自我给药戒断期间的敏感性。酒精的消耗量在这些 小鼠逆转了酒精戒断引起的机械性超敏反应。增加的疼痛敏感性， 经历戒断的小鼠与酒精依赖患者中增加的疼痛一致。另外我们 发现在与实验小鼠同室的对照“旁观者”小鼠中， 戒酒戒断小鼠痛觉过敏向旁观小鼠的社会传递 包括嗅觉线索。这种痛觉过敏的社会转移可能会影响“共同依赖”的家庭成员， 酗酒患者免疫组织化学分析显示背内侧下丘脑的差异激活， 前扣带和前岛叶皮质。我们假设大脑中被识别出的区域 在酒精戒断诱导的痛觉过敏和社会转移痛觉过敏中有差异。 本提案的目的是解决这一假设，并进一步描述酒精的现象 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实现：目标1 将通过以下方式进一步表征戒酒小鼠和旁观者小鼠中的痛觉过敏现象： 检查观察到的热痛觉过敏是否在雌性旁观者小鼠中被夸大，包括 消极情感状态、焦虑或压力反应，或与抑郁样行为共存。目标2将 测试酒精诱导的下丘脑背内侧神经元群的激活是否是必要的 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诱导的前扣带回和/或前扣带回神经元激活 这是调节疼痛敏感性的必要和充分条件。

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.