背根神经节嘌呤2X受体介导HIV及其治疗相关神经病理痛的作用机制和拮抗研究

Human immunodeficiency virus (HIV) infection and its highly active antiretroviral therapy often caused neuropathic pain. Neuropathic pain rat model, dorsal root ganglion (DRG) neuron or satellite glial cell (SGC) damage model caused by the HIV-1 envelope glycoprotein gp120 or gp120 combined with anti-retroviral drugs (ddC) treatment will be used in the project. Assuming of the project is that Purinergic 2(P2)X receptors, including P2X3 receptor in DRG neurons and P2X7 receptor in DRG SGC are involved in gp120 or gp120 plus ddC-mediated abnormal morphology and function between neuron-SGC in DRG, resulting in neuropathic pain. Our preliminary studies showed that gp120 or gp120 plus ddC upregulated the P2X3 expression of DRG neurons, P2X7 expression of DRG SGC (co-expressed with GFAP) in rat model. Project will observe the role of DRG P2X3, P2X7 receptors in neuropathic pain induced by gp120 or gp120 plus ddC and its possible mechanism, in order to understand the effect of P2X3, P2X7 antagonist or its small interfering RNA, natural medicine monomer on the DRG P2X3, P2X7 mediated neuropathic pain induced by gp120 or gp120 in combination with ddC. The application of nano materials of drug / gene collaborative targeting drug delivery system will be to observe the effects of the co-application of two or more drugs (such as P2X3, P2X7 receptor antagonists, or natural medicine monomer combinded with P2X3, P2X7 receptor small interfering RNA) on gp120 or gp120 plus ddC-mediated neuropathic pain involving P2X3, P2X7 in DRG. It will provide a new way for studying the prevention and treatment of the neuropathic pain caused by HIV infection and its highly active antiretroviral therapy.

人类免疫缺陷病毒(HIV)感染及其抗逆转录病毒治疗常引发神经病理痛。应用HIV-1包膜糖蛋白gp120、gp120合并抗逆转录病毒药物(ddC)所致神经病理痛大鼠或细胞损伤模型。项目假设背根神经节(DRG)嘌呤2(P2)X受体，包括神经元P2X3、卫星胶质细胞(SGC) P2X7受体介导gp120或gp120合并ddC损伤引起神经元-SGC间形态与功能异常，导致神经病理痛。预实验显示gp120或gp120合并ddC上调大鼠模型DRG神经元P2X3、SGC中P2X7受体(与GFAP共表达)水平。项目观察P2X3、P2X7拮抗或其小干扰RNA、天然药物单体对DRG中P2X3、P2X7介导gp120或gp120合并ddC引发神经病理痛的效应。应用纳米材料性药物/基因协同靶向给药系统，观察P2X3、P2X7拮抗剂、天然药物单体与P2X3、P2X7小干扰RNA共用的作用，进而为其防治研究提供新途径。

人类免疫缺陷病毒(HIV)感染及其抗逆转录病毒治疗常引发神经病理痛。应用HIV-1包膜糖蛋白gp120、gp120合并抗逆转录病毒药物(ddC)所致神经病理痛大鼠或细胞损伤模型，研究发现A317491抑制背根神经节P2X3受体介导HIV糖蛋白120神经病理痛；亮蓝G、白藜芦醇分别抑制P2X7受体介导HIV糖蛋白120神经病理痛。穿心莲内酯抑制P2X7受体介导的HIV gp120加ddC诱发神经病理痛。背根神经节（DRG）卫星神经胶质细胞（SGC）P2Y12受体上调涉及HIV糖蛋白120诱导大鼠神经病理痛和HIV糖蛋白120加2',3'-二脱氧胞苷（ddC）诱发神经病理性疼痛，嘌呤2Y12短发夹核糖核酸（shRNA）处理降低背根神经节卫星胶质细胞P2Y12受体表达和缓解HIV糖蛋白120诱导大鼠神经病理痛及HIV糖蛋白120加2′,3′-二脱氧胞苷（ddC）诱发神经病理痛。P2X4受体参与gp120诱导的背根神经节卫星胶质细胞（SGCs）焦亡病理变化。长非编码RNA uc.48 +调节泛素-蛋白酶体系统减轻P2Y12受体介导的HIV gp120相关神经病理痛。以上研究结果将为探究HIV 感染并发的神经病理痛及抗逆转录病毒治疗引发的神经病理痛的发病机制及新防治药物研究提供实验基础。