Gene therapy of HIV-neuropathic pain with morphine tolerance

描述（由申请人提供）：阿片类药物滥用和人类免疫缺陷病毒（HIV）感染/艾滋病是两个主要的公共卫生问题。HIV相关感觉神经病变（HIV-SN）是HIV感染最常见的神经系统并发症。HIV-SN的症状以远端神经性疼痛为主。大量证据表明脊髓神经胶质细胞活化/产物参与神经性疼痛的发病机制，最近的数据表明，神经系统中的常驻免疫细胞可能代表阿片类药物滥用和HIV-SN之间的重要交叉点。为了研究这两个过程（慢性阿片类药物使用和疼痛的HIV-SN）之间的相互作用，我们提出了一系列实验来严格检验这一假设，即胶质细胞的激活在慢性吗啡治疗与HIV-SN神经性疼痛的相互作用中起着关键作用。在具体目标1中，我们将使用行为分析和Western印迹、免疫组织化学和ELISA测量胶质细胞活化来确定吗啡耐受和HIV-SN神经病理性疼痛的影响。在具体目标2中，我们将通过检查在脊髓中使用单纯疱疹病毒载体的基因转移抑制胶质细胞活化/产物是否减少患有HIV-SN神经性疼痛的吗啡耐受动物的疼痛来严格检验该假设。这一系列的行为，神经化学和免疫组织化学研究将提供重要的新信息的机制，增强胶质细胞活化释放促炎细胞因子诱导脊髓敏化，并可能指向新的治疗方法来治疗吗啡耐受性疼痛。这些研究将为今后艾滋病相关疼痛的机制和治疗的长期研究提供初步数据。公共卫生相关性：该提案将研究HIV-神经性疼痛和吗啡耐受性的相互作用机制。该研究可能为吗啡耐受性治疗HIV-神经病理性疼痛提供新的途径。

DESCRIPTION (provided by applicant): Opiate drug abuse and human immunodeficiency virus (HIV) infection/AIDS are two major public health problems. HIV-associated sensory neuropathy (HIV-SN) is the most common neurological complication of HIV infection. The symptoms of HIV-SN are dominated by distal neuropathic pain. Substantial evidence implicates spinal glia activation/products in the pathogenesis of neuropathic pain, and recent data suggests that resident immune cells in the nervous system may represent an important point of intersection between opiate abuse and HIV-SN. In order to investigate the interaction between these two processes (chronic opioid use and painful HIV-SN) we propose a series of experiments to critically test the hypothesis that activation of glia plays a key role in the interaction of chronic morphine treatment with HIV-SN neuropathic pain. In Specific Aim 1 we will define the effects of morphine tolerance and HIV-SN neuropathic pain using behavioral analysis and Western blot, immunohostochemistry and ELISA measures of glial activation. In Specific Aim 2 we will critically test the hypothesis by examining whether inhibition of glial activation/products using herpes simplex virus vector-based gene transfer in the spinal cord reduces pain in morphine tolerant animals with HIV-SN neuropathic pain. This series of behavioral, neurochemical and immunohistochemical studies will provide important new information about the mechanisms by which enhanced glia activation releasing proinflammatory cytokines induces spinal sensitization, and may point towards novel therapeutic approaches to treat that pain in morphine tolerance. These studies will provide preliminary data for future long-term research of the mechanisms and treatment of HIV-related pain. PUBLIC HEALTH RELEVANCE: This proposal will investigate the mechanism of interaction of HIV-neuropathic pain and morphine tolerance. The research may provide a novel approach to treatment of HIV-neuropathic pain with morphine tolerance.