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: 9084524
• 负责人: SHAO-JUN TANG
• 金额: $ 37.87万
• 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/9084524
• 关键词: Acquired Immunodeficiency Syndrome; Adverse effects; Analgesics; Astrocytes; Biological; CCR5 gene; Chemosensitization; Chronic; Clinical; Clinical Data; Consequences of HIV; Cytokine Signaling; Data; Development; Drug Prescriptions; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Health; 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; Reactive Oxygen Species; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Spinal cord posterior horn; TLR4 gene; Testing; Work; base; chronic pain; cytokine; improved; inhibitor/antagonist; mouse model; mu opioid receptors; novel; novel strategies; opioid use; prevent; receptor; therapy design

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(申请人提供)：数百万HIV-1/AIDS患者遭受慢性疼痛。在这些患者中，吗啡是一种常见的止痛药。具有讽刺意味的是，临床数据表明，反复使用吗啡治疗会导致慢性疼痛状态加剧。这一问题具有非常重要的临床意义，因为它表明，接受吗啡止痛的HIV-1患者实际上可能会因为治疗而出现更多疼痛。因此，迫切需要了解长期使用吗啡是如何导致HIV-1患者出现这种情况的。使用与HIV-1人类患者疼痛相关病理相似的广泛异常的小鼠模型，我们观察到长期给予吗啡增强了HIV-1 gp120(I.T.)诱导的疼痛。与此同时，我们发现，长期使用吗啡还显著增强了gp120(I.T.)诱导的脊髓背角(SDH)星形胶质细胞的激活，SDH是中枢第一个疼痛处理中心。我们最近的工作表明，星形胶质细胞的激活在HIV-1患者的疼痛发病机制中起着关键作用。因此，吗啡增强星形胶质细胞的激活可能为吗啡增强HIV相关疼痛提供了重要的细胞基础。这个项目的目的是了解gp120-吗啡在SDH中星形胶质细胞激活中的相互作用的机制和后果。我们的初步数据显示，长期给予gp120和吗啡协同上调Wnt5a，这是一种分泌的信号蛋白，激活SDH中的星形胶质细胞，但不激活小胶质细胞。基于大量的初步数据，我们假设gp120和吗啡通过刺激Wnt5a信号协同激活星形胶质细胞，激活的星形胶质细胞通过促进细胞因子信号通路增强gp120诱导的痛敏。这一假设将在拟议的项目中根据三个具体目标进行检验。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的作用。最后，在目标3中，我们将确定星形胶质细胞的激活在gp120诱导的痛觉过敏的吗啡增强中的作用。这项研究的结果将显著提高我们对gp120和吗啡相互作用激活SDH中星形胶质细胞的机制的理解。这一结果还将帮助我们了解长期使用吗啡是如何增强艾滋病毒相关疼痛的。这项研究对于开发新的方法来预防HIV-1患者的吗啡增强痛觉过敏具有重要的潜力。