HIV-1 Infection and the Peripheral Nervous System

描述（由申请人提供）：本拨款提案旨在确定与HIV-1感染相关的神经性疼痛发展的潜在机制以及核苷类逆转录酶抑制剂（NRTIs）的治疗。我们观察到，在不同的情况下，趋化细胞因子（趋化因子）受体在背根神经节中表达。在正常情况下，趋化因子SDF-1/CXCL12的受体CXCR4在DRG神经元和胶质细胞中表达。SDF-1也组成性表达。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，在几种神经性疼痛的啮齿动物模型中，某些趋化因子如MCP- 1/CCL2及其受体如CCR2的表达在DRG神经元和胶质细胞中大大增加。在DRG神经元上调趋化因子后，趋化因子被包装到突触囊泡中，并可以通过去极化刺激从DRG神经元和神经胶质细胞中以Ca依赖的方式释放。神经性疼痛动物的DRG神经元被趋化因子如MCP-1强烈去极化。我们观察到，用HIV-1包膜蛋白gp120治疗周围神经会增加DRG中MCP-1/CCR2的表达，这与神经性疼痛有关。我们还观察到，用NRTIs治疗啮齿动物会产生神经性疼痛，这与DRG神经元和胶质细胞中CXCR4受体的上调有关。抑制CXCR4功能可抑制NRTI相关的疼痛超敏反应。叙述：在这项拨款申请中，我们将确定- 1)神经胶质和神经元CXCR4表达在NRTI诱导的疼痛超敏反应发展中的相对作用。2) DRG中CXCR4受体上调在NRTIs和HIV-1感染产生疼痛超敏反应的协同作用中的作用。趋化因子作为新型神经递质在DRG中产生神经性疼痛的作用。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。由此得出的数据将为治疗这些疾病提供新的途径。

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.