Neuropathic mechanisms and gene therapy on opioid dependence

项目总结： 阿片依赖是一种慢性复发性疾病，以强迫寻求和使用药物为特征。 阿片依赖导致身体过度依赖(戒断综合症)。虽然 对阿片类药物的心理依赖是依赖/滥用、身体依赖本身的一个重要特征 (戒断综合症)是强迫吸毒行为和短期复发的主要原因。 遗憾的是，阿片类药物在阿片依赖病理变化中的作用机制尚不清楚 详细地说。最近的研究表明，慢性吗啡可诱导促炎细胞因子的释放(如 肿瘤坏死因子)。氧化应激可能参与海洛因依赖/戒断的过程。然而，非常 很少有研究涉及这些神经胶质细胞对中枢神经系统神经元的确切作用机制。 阿片类药物戒断时的TNFR、钙和ROS反应。PAG在阿片类药物表达中的作用 研究已经提出了停药的建议，但我们对其详细的分子机制知之甚少。在这里，我们 假设胶质细胞的激活会导致促炎细胞因子的释放，而神经元 细胞因子受体激活诱导线粒体ROS和pCREB(药物滥用行为的关键蛋白) 吗啡戒断的发展。特定目标1，测试神经胶质细胞TLR4激活是否诱导释放 细胞因子在吗啡戒断中的作用。特定目的2，测试细胞因子受体的激活是否会诱导 PAG中吗啡戒断过程中线粒体ROS的变化具体目标3，测试线粒体ROS在 PAG通过pCREB参与MW。该提案将使用药理学、分子生物学 生物学、免疫组织化学、细胞类型靶向基因转染、图像密度分析等完成 新奇的假说。这些研究的结果将为阿片类药物的发病机制提供重要的见解。 并可能为阿片类药物依赖的新疗法提供临床前证据。

Project Summary: Opioid dependence is a chronic and relapsing disease and characterized by compulsive drug seeking and use. Opioid dependence results in excessive degrees of physical dependence (withdrawal syndrome). Although psychological dependence on opioids is an important feature of dependence/abuse, physical dependence itself (withdrawal syndrome) is a major cause of compulsive drug-taking behavior and short term relapse. Unfortunately, the mechanism of opioid in the pathological changes in opioid dependence is not yet understood in detail. Recent studies show that chronic morphine induces release of proinflammatory cytokines (e.g. TNF¿). Oxidative stress may participate in the process of dependence /withdrawal of heroin. However, very few studies have addressed the precise mechanisms by which these glial elements contribute to CNS neuronal TNFR, calcium and ROS response in opioid withdrawal. The role of the PAG in the expression of opioid withdrawal has been suggested by studies, but we know little of the detailed molecular mechanisms. Here, we hypothesize that glial activation resulting in the release of proinflammatory cytokines, and that neurons activated by cytokine receptor induce mitochondrial ROS and pCREB (a key protein in drug abuse behavior) in the development of morphine withdrawal. Specific Aim 1, To test whether glial TLR4 activation induces release of cytokine in morphine withdrawal. Specific Aim 2, To test whether activation of cytokine receptor induces mitochondrial ROS in morphine withdrawal in the PAG. Specific Aim 3, To test whether mitochondrial ROS in the PAG is involved in MW through the pCREB. The proposal will use assays of pharmacology, molecular biology, immunohistochemistry, cell type-targeting gene transfection, and imaging density analysis to complete the novel hypothesis. The results of these studies will provide important insights into the pathogenesis of opioid abuse, and may provide preclinical evidence for a novel therapy of opioid dependence.