Interplay of HIV-1 gp120 and opioids in astrocyte activation

HIV-1 gp120 和阿片类药物在星形胶质细胞激活中的相互作用

• 批准号: 8584926
• 负责人: SHAO-JUN TANG
• 金额: $ 38.6万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584926
• 关键词: Acquired Immunodeficiency Syndrome; Adverse effects; Analgesics; Astrocytes; Biological; CCR5 gene; Chemokine (C-C Motif) Receptor 5; Chemosensitization; Chronic; Clinical; Clinical Data; Consequences of HIV; Cytokine Signaling; Data; Development; Drug Prescriptions; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Human; Hyperalgesia; Infection; Knockout Mice; Lead; Light; Mediating; Microglia; Mitochondria; Molecular; Morphine; Neurons; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Process; Proteins; RORA gene; Reactive Oxygen Species; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Spinal cord posterior horn; Testing; Work; base; chronic pain; cytokine; improved; inhibitor/antagonist; mouse model; mu opioid receptors; novel; novel strategies; prevent; public health relevance; receptor; therapy design; toll-like receptor 4

DESCRIPTION (provided by applicant): Millions of HIV-1/AIDS patients suffer chronic pain. Morphine is a common analgesic for pain relief in these patients. Ironically, clinical data indicat that repeated morphine treatment leads a heightened chronic pain state. This problem is of great clinical importance since it suggests that HIV-1 patients receiving morphine to relieve pain may actually develop more pain as a result of treatment. Thus, there is a compelling need to understand how chronic morphine use causes this condition in HIV-1 patients. Using a mouse model that develops extensive abnormalities similar to the pain-related pathologies in HIV-1 human patients, we observed that chronic morphine administration potentiates HIV-1 gp120 (i.t.)-induced pain. Concomitantly, we found that chronic use of morphine also dramatically enhances gp120 (i.t.)-induced astrocyte activation in the spinal cord dorsal horn (SDH), the first pain processing center in the CNS. Our recent work suggests a key role of astrocyte activation in pain pathogenesis in HIV-1 patients. Hence, the morphine-enhanced astrocyte activation may provide an important cellular basis for morphine to potentiate HIV-related pain. The goal of this project is to understand the mechanism and consequences of the gp120-morphine interplay in astrocyte activation in the SDH. Our preliminary data show that chronic administration of gp120 and morphine cooperatively up-regulate Wnt5a, a secreted signaling protein that activates astrocytes but not microglia in the SDH. Based on ample preliminary data, we hypothesize that gp120 and morphine synergistically activate astrocytes by stimulating Wnt5a signaling and that the activated astrocytes enhance gp120-induced hyperalgesia by promoting cytokine signaling. This hypothesis will be tested in the proposed project under three specific aims. In Aim 1, we will identify the molecular pathways through which the gp120-morphine interaction stimulates astrocyte activation in the SDH. In Aim 2, we will establish the role of the mitochondria-inflammasome axis in control of cytokine signaling in astrocytes activated by gp120 and morphine. Finally in Aim 3, we will determine the contribution of astrocyte activation to the morphine potentiation of gp120-induced hyperalgesia. Results from this study will significantly improve our understanding of the mechanism by which the interplay of gp120 and morphine activates astrocytes in the SDH. The results will also help us understand how chronic morphine use enhances HIV-associated pain. The research has significant potential for the development of novel approaches to prevent the morphine-potentiation of hyperalgesia in HIV-1 patients.

描述（由申请人提供）：数百万 HIV-1/AIDS 患者遭受慢性疼痛。吗啡是缓解这些患者疼痛的常用镇痛药。具有讽刺意味的是，临床数据表明重复吗啡治疗会导致慢性疼痛状态加剧。这个问题具有重要的临床意义，因为它表明接受吗啡缓解疼痛的 HIV-1 患者实际上可能会因治疗而出现更多的疼痛。因此，迫切需要了解长期使用吗啡如何导致 HIV-1 患者出现这种情况。使用小鼠模型，该模型出现与 HIV-1 人类患者疼痛相关病理类似的广泛异常，我们观察到长期服用吗啡会增强 HIV-1 gp120 (i.t) 引起的疼痛。与此同时，我们发现长期使用吗啡也会显着增强 gp120 (i.t.) 诱导的脊髓背角 (SDH) 星形胶质细胞的激活，SDH 是中枢神经系统的第一个疼痛处理中心。我们最近的工作表明星形胶质细胞激活在 HIV-1 患者疼痛发病机制中发挥着关键作用。因此，吗啡增强的星形胶质细胞活化可能为吗啡增强 HIV 相关疼痛提供重要的细胞基础。该项目的目标是了解 gp120-吗啡在 SDH 星形胶质细胞激活中相互作用的机制和后果。我们的初步数据表明，长期服用 gp120 和吗啡会协同上调 Wnt5a，Wnt5a 是一种分泌的信号蛋白，可激活星形胶质细胞，但不激活 SDH 中的小胶质细胞。基于大量的初步数据，我们假设 gp120 和吗啡通过刺激 Wnt5a 信号传导协同激活星形胶质细胞，并且激活的星形胶质细胞通过促进细胞因子信号传导增强 gp120 诱导的痛觉过敏。该假设将在拟议项目中根据三个具体目标进行测试。在目标 1 中，我们将确定 gp120-吗啡相互作用刺激 SDH 中星形胶质细胞激活的分子途径。在目标 2 中，我们将确定线粒体炎症体轴在 gp120 和吗啡激活的星形胶质细胞中控制细胞因子信号传导中的作用。最后，在目标 3 中，我们将确定星形胶质细胞激活对 gp120 诱导的痛觉过敏吗啡增强的贡献。这项研究的结果将显着提高我们对 gp120 和吗啡相互作用激活 SDH 星形胶质细胞机制的理解。研究结果还将帮助我们了解长期使用吗啡如何增强与艾滋病毒相关的疼痛。该研究对于开发预防 HIV-1 患者痛觉过敏吗啡增强的新方法具有巨大潜力。