Neuropathic mechanisms and gene therapy on opioid dependence

阿片类药物依赖的神经病理机制和基因治疗

基本信息

批准号：
8631473
负责人：
SHUANGLIN HAO
金额：
$ 35.64万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631473
关键词：
Address Agonist Antioxidants Behavior Behavioral Binding Biological Assay CREB1 gene Calcium Cells Chronic Chronic Disease Cyclic AMP Cyclic AMP-Responsive DNA-Binding Protein Cytokine Receptors Dependence Development Drug Addiction Drug abuse Elements Endoplasmic Reticulum Gene Targeting HSV vector Healthcare Systems Heroin Hyperalgesia Image Image Analysis Immunohistochemistry Manganese Superoxide Dismutase Mediating Midbrain structure Mitochondria Molecular Molecular Biology Morphine Mus Myelogenous Neuraxis Neuroglia Neurons Neuropathy Opiate Addiction Opiates Opioid Oxidative Stress Pathogenesis Pathway interactions Pharmaceutical Preparations Pharmacology Phosphorylation Physical Dependence Process Production Proteins Psychological Dependence Public Health Reactive Oxygen Species Recurrent disease Relapse Role Second Messenger Systems Signal Transduction Simplexvirus Substance Withdrawal Syndrome Superoxides TNF gene Testing Transfection Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Up-Regulation Withdrawal addiction calcium uniporter cell type cytokine density drug abuse prevention gene therapy insight midbrain central gray substance mu opioid receptors neurobiological mechanism neuropathology nonmedical use novel novel therapeutics opioid abuse opioid withdrawal overexpression pre-clinical public health relevance receptor receptor density response second messenger toll-like receptor 4 uptake

项目摘要

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.

项目摘要：阿片类药物依赖性是一种慢性疾病，其特征是寻求和使用。阿片类药物依赖性在过度的身体依赖程度（戒断综合征）中导致。尽管对阿片类药物的心理依赖是依赖/滥用，身体依赖本身的重要特征（戒断综合征）是强迫吸毒行为和短期缓解的主要原因。不幸的是，尚不清楚蛋白质依赖性病理学变化中绿o的机制详细。最近的研究表明，慢性吗啡诱导促炎细胞因子的释放（例如， tnf¿）。氧化应激可能参与海洛因的依赖 /戒断过程。但是，非常很少有研究解决这些神经胶质元件有助于CNS神经元的确切机制 TNFR，钙和ROS反应中的钙毒素戒断中。 PAG在卵虫类表达中的作用戒断是通过研究提出的，但我们对详细的分子机制几乎不知道。在这里，我们假设神经胶质激活导致促炎细胞因子释放，并且神经元通过细胞因子受体诱导线粒体ROS和PCREB（药物滥用行为的关键蛋白）激活吗啡戒断的发展。特定目标1，以测试Glial TLR4激活是否诱导释放特定目标2，以测试吗啡戒断中细胞因子受体的激活。 PAG中吗啡的线粒体ROS。特定目标3，以测试线粒体ROS是否在 PAG通过PCREB参与MW。该提案将使用药理学分子的测定法生物学，免疫组织化学，细胞类型靶向基因翻译和成像密度分析以完成新的假设。这些研究的结果将为阿片类药物的发病机理提供重要的见解滥用，可能为阿片类药物依赖性的新疗法提供临床前证据。