Gene therapy of HIV-neuropathic pain with morphine tolerance

描述(申请人提供)：鸦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(HIV-SN)是HIV感染最常见的神经系统并发症。HIV-SN的症状以远端神经病理性疼痛为主。大量证据表明脊髓胶质细胞激活/产物参与神经病理性疼痛的发病机制，最近的数据表明神经系统中的常驻免疫细胞可能是阿片类药物滥用和HIV-SN的一个重要交叉点。为了研究这两个过程(慢性阿片类药物使用和痛苦的HIV-SN)之间的相互作用，我们提出了一系列实验，以关键地检验胶质细胞的激活在慢性吗啡治疗与HIV-SN神经病理性疼痛的相互作用中起关键作用的假说。在具体目标1中，我们将使用行为分析和免疫印迹、免疫组织化学和ELISA法确定吗啡耐受和HIV-SN神经病理性疼痛的影响。在特定的目标2中，我们将通过检测在脊髓中使用基于单纯疱疹病毒载体的基因转移抑制胶质细胞激活/产物是否减少患有HIV-SN神经病理性疼痛的吗啡耐受动物的疼痛来关键地检验这一假说。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，通过增强胶质细胞激活释放促炎细胞因子诱导脊髓敏化，并可能指向治疗吗啡耐受疼痛的新方法。这些研究将为未来艾滋病毒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：这项提案将调查HIV-神经病理性疼痛和吗啡耐受相互作用的机制。本研究可能为治疗吗啡耐受的HIV神经病理性疼痛提供一种新的方法。

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.