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: 8840924
• 负责人: SHAO-JUN TANG
• 金额: $ 37.68万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840924
• 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; 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; 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; 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）：数百万的HIV-1/AIDS患者患有慢性疼痛。吗啡是这些患者缓解疼痛的常见镇痛药。具有讽刺意味的是，临床数据表明重复吗啡治疗导致慢性疼痛状态升高。这个问题非常重要，因为它表明接受吗啡以缓解疼痛的HIV-1患者实际上可能由于治疗而产生更多的疼痛。因此，迫切需要了解慢性吗啡的使用如何在HIV-1患者中引起这种情况。使用与HIV-1人类患者相似的广泛异常的小鼠模型，我们观察到慢性吗啡给药增强了HIV-1 GP120（I.T。） - 诱导的疼痛。同时，我们发现吗啡的长期使用也大大增强了GP120（I.T。） - 脊髓背侧角（SDH）中的星形胶质细胞激活，CNS中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患者疼痛发病机理中的关键作用。因此，吗啡增强的星形胶质细胞激活可能为形态增强HIV相关疼痛的重要细胞基础。该项目的目的是了解SDH中星形胶质细胞激活中GP120摩尔吗啡相互作用的机制和后果。我们的初步数据表明，GP120和吗啡的长期给药合作上调Wnt5a，这是一种分泌的信号传导蛋白，可激活SDH中的星形胶质细胞但不激活小胶质细胞。基于足够的初步数据，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，并且活化的星形胶质细胞通过促进细胞因子信号传导来增强GP120诱导的HyperSTERGESIA。该假设将在拟议项目中以三个特定目的进行检验。在AIM 1中，我们将确定GP120-寄电相互作用刺激SDH中星形胶质细胞激活的分子途径。在AIM 2中，我们将确定线粒体 - 炎症轴控制GP120和吗啡激活的星形胶质细胞中细胞因子信号传导的作用。最后，在AIM 3中，我们将确定星形胶质细胞激活对GP120诱导的痛觉过敏的吗啡增强的贡献。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中星形胶质细胞的机制的理解。结果还将有助于我们了解慢性吗啡的使用如何增强与HIV相关的疼痛。这项研究具有开发新方法的巨大潜力，以防止HIV-1患者中痛觉过敏的吗啡抑制。