HIV-1 Infection and the Peripheral Nervous System

描述(由申请者提供)：这项赠款提案旨在确定与HIV-1感染相关的神经病理性疼痛的潜在机制及其核苷逆转录酶抑制剂(NRTI)的治疗。我们观察到趋化细胞因子(趋化因子)的受体在不同环境下由背根神经节的细胞表达。在正常情况下，趋化因子SDF-1/CXCL12的受体CXCR4由DRG神经元和神经胶质细胞表达。SDF-1也是结构性表达的。其他类型的趋化因子及其受体通常不在这些细胞中表达。我们观察到，在几种神经病理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的表达被背根神经节神经元和胶质细胞大大增强。在被DRG神经元上调后，趋化因子被包装成突触小泡，并可通过去极化刺激从DRG神经元释放，并以钙依赖的方式从胶质细胞释放。患有神经病理性疼痛的动物的DRG神经元被趋化因子如MCP-1强烈去极化。我们观察到，用HIV-1包膜蛋白gp120处理周围神经时，DRG中MCP-1/CCR2的表达增加，与神经病理性疼痛有关。我们还观察到，用NRTIs治疗啮齿动物会产生神经病理性疼痛，这与DRG神经元和神经胶质细胞中CXCR4受体的上调有关。抑制CXCR4功能可抑制NRTI相关的痛敏反应。叙述：在这项拨款提案中，我们将确定：1)神经胶质细胞和神经元CXCR4表达在NRTI诱导的疼痛过敏发展中的相对作用。2)背根神经节CXCR4受体上调在NRTIs和HIV-1感染在产生疼痛过敏中的协同作用中的作用。3)趋化因子作为新的神经递质在DRG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感染艾滋病毒-1和抗艾滋病毒-1药物治疗如何产生慢性疼痛综合征。由此产生的数据将为这些疾病的治疗提供新的方法。

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.