Cooperative mechanisms of HIV and opiods in pain pathogenisis

摘要 基于阿片类药物的镇痛药通常用于暂时缓解 HIV-1/AIDS 患者的严重疼痛。 然而，最近的临床数据表明，长期阿片类药物治疗会导致疼痛加剧 （痛觉过敏）。这种使人衰弱的副作用需要增加镇痛药的剂量才能缓解。 有效，因此可能直接导致阿片类药物过量和流行。临床上为了预防这种情况 重要的副作用，有必要了解长期使用阿片类药物如何导致艾滋病毒痛觉过敏 患者。 HIV-1 gp120 小鼠模型再现了人类 HIV 患者广泛的疼痛相关病理 我们模拟吗啡加剧 gp120 引起的疼痛。该项目的目标是阐明 吗啡增强艾滋病毒相关疼痛的致病机制。我们之前的工作表明 脊髓背角 (SDH) 的神经炎症是 HIV 患者的主要神经病理学 神经性疼痛。根据我们的初步研究，我们认为神经炎症是一种趋同性炎症 gp120 和阿片类药物合作增强病理性疼痛的神经病理学机制。我们的 初步研究进一步表明，gp120 和吗啡通过重叠但不同的作用引起神经炎症 分子途径。我们假设吗啡和 gp120 通过共同激活来协同疼痛发病机制 神经炎症途径。拟议的研究旨在通过阐明以下内容来检验这一中心假设： 这些途径在 gp120 和吗啡单独或组合诱导的疼痛发病机制中的作用。我们会 使用蛋白质分析、单细胞转录组分析、全细胞补丁的跨学科方法 记录和行为测试。这些研究的结果将显着提高我们对 吗啡加剧艾滋病毒相关疼痛的机制。

ABSTRACT Opioid-based analgesics are commonly used for temporal relief of severe pain in HIV-1/AIDS patients. However, recent clinical data show that chronic opioid treatment causes a heightened pain state (hyperalgesia). This debilitating side effect requires escalating dosages of the analgesics in order to be effective, and thus may directly contribute to opioid overdose and epidemics. To prevent this clinically important side effect, it is necessary to understand how chronic use of opioids causes hyperalgesia in HIV patients. In the HIV-1 gp120 mouse model that recapitulates extensive pain-related pathologies of HIV human patients, we simulate morphine exacerbation of gp120-induced pain. The goal of this project is to elucidate the pathogenic mechanism by which morphine potentiates HIV-associated pain. Our prior work reveals that neuroinflammation in the spinal cord dorsal horn (SDH) is a cardinal neuropathology in HIV patients with neuropathic pain. Based on our preliminary studies, we propose that neuroinflammation is a convergent neuropathological mechanism by which gp120 and opioids cooperate to potentiate pathological pain. Our preliminary studies further show that gp120 and morphine elicit neuroinflammation via overlapped but distinct molecular pathways. We hypothesize that morphine and gp120 synergize pain pathogenesis by co-activating the neuroinflammatory pathways. The proposed research is to test this central hypothesis by elucidating the roles of these pathways in pain pathogenesis induced by gp120 and morphine alone or in combination. We will use interdisciplinary approaches of protein analysis, single cell transcriptome analysis, whole cell patch recording and behavioral testing. Results from these studies will significantly improve our understanding of the mechanism by which morphine exacerbates HIV-associated pain.