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。吗啡是一种常见的止痛药，用于缓解这些患者的疼痛。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，迫切需要了解慢性吗啡使用如何导致HIV-1患者出现这种情况。使用小鼠模型，该模型发展了与HIV-1人类患者中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HIV-1 gp 120（i.t.）诱发疼痛。与此同时，我们发现长期使用吗啡也显著增强gp 120（i.t.）诱导脊髓背角（SDH）中的星形胶质细胞活化，SDH是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活化在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活化可能为吗啡增强HIV相关疼痛提供了重要的细胞基础。本项目的目标是了解SDH中星形胶质细胞活化中gp 120-吗啡相互作用的机制和后果。我们的初步数据表明，长期管理的gp 120和吗啡合作上调Wnt 5a，分泌的信号蛋白，激活星形胶质细胞，但不是小胶质细胞在SDH。基于大量的初步数据，我们假设gp 120和吗啡协同激活星形胶质细胞通过刺激Wnt 5a信号和激活的星形胶质细胞增强gp 120诱导的痛觉过敏通过促进细胞因子信号。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gp 120-吗啡相互作用刺激SDH中星形胶质细胞活化的分子途径。在目标2中，我们将建立在gp 120和吗啡激活的星形胶质细胞中的细胞因子信号传导的控制中的炎症-炎性小体轴的作用。最后在目标3中，我们将确定星形胶质细胞活化对gp 120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的理解的机制，其中gp 120和吗啡的相互作用激活星形胶质细胞在SDH。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。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。

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.