Interplay of HIV-1 gp120 and opioids in astrocyte activation

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，反复吗啡治疗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产生更多的疼痛。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。通过小鼠模型，出现了与HIV-1人类患者疼痛相关病理相似的广泛异常，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，我们发现长期使用吗啡也显著增强gp120 （i.t）诱导的脊髓背角（SDH）的星形胶质细胞激活，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的关键作用。因此，吗啡增强的星形胶质细胞激活可能为吗啡增强hiv相关疼痛提供了重要的细胞基础。该项目的目的是了解gp120-吗啡在SDH星形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，长期给药gp120和吗啡协同上调Wnt5a，这是一种在SDH中激活星形胶质细胞而不激活小胶质细胞的分泌信号蛋白。基于大量的初步数据，我们假设gp120和吗啡通过刺激Wnt5a信号通路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诱导的痛觉过敏。这一假设将在三个具体目标下的拟议项目中进行测试。在Aim 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Aim 2中，我们将确定线粒体-炎性体轴在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Aim 3中，我们将确定星形胶质细胞激活对吗啡增强gp120诱导的痛觉过敏的贡献。本研究结果将显著提高我们对gp120和吗啡相互作用激活SDH星形胶质细胞的机制的理解。研究结果也将帮助我们理解长期使用吗啡是如何增强hiv相关疼痛的。这项研究对于开发新的方法来预防HIV-1患者痛觉过敏的吗啡增强具有重要的潜力。

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.