HIV-1 Infection and the Peripheral Nervous System

描述（由申请人提供）：该资助提案旨在确定与HIV-1感染相关的神经性疼痛的发展机制及其核苷逆转录酶抑制剂（NRTI）治疗。我们观察到背根神经节细胞在不同的环境下表达趋化性细胞因子受体。在正常条件下，趋化因子SDF-1/CXCL 12的受体CXCR 4由DRG神经元和神经胶质表达。SDF-1也是组成型表达的。其他类型的趋化因子及其受体通常不被这些细胞表达。我们观察到，在几种啮齿动物神经病理性疼痛模型中，某些趋化因子如MCP- 1/CCL 2及其受体如CCR 2的表达被DRG神经元和神经胶质细胞大大增加。在它们被DRG神经元上调后，趋化因子被包装到突触囊泡中，并且可以通过去极化刺激从DRG神经元释放，并且以Ca依赖性方式从神经胶质细胞释放。来自患有神经性疼痛的动物的DRG神经元被趋化因子如MCP-1强烈去极化。我们已经观察到用HIV-1包膜蛋白gp 120治疗外周神经在与神经性疼痛相关的DRG中产生MCP-1/CCR 2的表达增加。我们还观察到用NRTI治疗啮齿动物产生神经性疼痛，并且这与DRG神经元和神经胶质中CXCR 4受体的上调有关。抑制CXCR 4功能可抑制NRTI相关的疼痛超敏反应。叙述：在这项资助计划中，我们将确定：1）神经胶质和神经元CXCR 4表达在NRTI诱导的疼痛超敏反应发展中的相对作用。2)DRG中CXCR 4受体上调在NRTI和HIV-1感染产生疼痛超敏反应的协同作用中的作用3)趋化因子作为新型神经递质在DRG中产生神经病理性疼痛中的作用。拟议的研究将帮助我们了解HIV-1感染和抗HIV-1药物治疗如何产生慢性疼痛综合征。由此产生的数据将提出治疗这些疾病的新方法。

DESCRIPTION (provided by applicant): This grant proposal seeks to determine the mechanisms underlying the development of neuropathic pain in association with HIV-1 infection and its treatment with Nucleoside Reverse Transcriptase Inhibitors (NRTIs). We observed that receptors for CHEMOtactic cytoKINES (chemokines) are expressed by cells in the Dorsal Root Ganglia under different circumstances. Under normal conditions CXCR4, the receptors for the chemokine SDF-1/CXCL12, are expressed by DRG neurons and glia. SDF-1 is also constitutively expressed. Other types of chemokines and their receptors are not normally expressed by these cells. We observed that in several rodent models of neuropathic pain the expression of certain chemokines such as MCP- 1/CCL2 and their receptors such as CCR2, is greatly increased by DRG neurons and glia. Following their upregulation by DRG neurons, chemokines are packaged into synaptic vesicles and can be released from DRG neurons by depolarizing stimuli and from glial cells in a Ca dependent fashion. DRG neurons from animals with neuropathic pain are strongly depolarized by chemokines such as MCP-1. We have observed that treatment of peripheral nerves with the HIV-1 envelope protein gp120 produces increased expression of MCP-1/CCR2 in the DRG in association with neuropathic pain. We also observed that treatment of rodents with NRTIs produces neuropathic pain and that this is associated with upregulation of CXCR4 receptors in DRG neurons and glia. Inhibition of CXCR4 function inhibits NRTI associated pain hypersensitivity. Narrative: In this grant proposal we shall determine- 1) The relative roles of glial and neuronal CXCR4 expression in the development of NRTI induced pain hypersensitivity. 2) The role of CXCR4 receptor upregulation in the DRG in the synergistic effects of NRTIs and HIV-1 infection in producing pain hypersensitivity. 3) The role of chemokines as novel neurotransmitters in the DRG in producing neuropathic pain. The proposed studies will help us to understand how infection with HIV-1 and treatment with anti-HIV-1 drugs produces chronic pain syndromes. The resulting data will suggest novel approaches to the treatment of these disorders.