Cellular and circuitry mechanisms of NRTI-induced pain pathogenesis in the context of opioids and HIV

项目总结 联合抗逆转录病毒疗法(CART)是目前治疗人类免疫缺陷病毒的一线疗法 (HIV)感染。不幸的是，CART与各种形式的HIV相关神经疾病有关。疼痛 是最常见的神经系统并发症，显著降低了许多人的生活质量 与艾滋病毒(PLWH)有关，新出现的证据表明，CART在糖尿病疼痛的发生中起关键作用 PLWH。然而，CART促进疼痛发生的机制仍不完全清楚。 而且基于原理的有效辅助治疗是不可用的。在这个项目中，我们的目标是阐明致病因子 核苷逆转录酶抑制剂的作用机制--抗逆转录病毒药物的基石 在CART方案中，并引起神经病理性疼痛。因为购物车上的PLWH通常接触阿片类药物和 导致疼痛的HIV-1 gp120蛋白，我们还将调查潜在的致病相互作用 NRTI和阿片类药物或gp120。我们的数据显示，单独给小鼠注射NRTIs、吗啡或gp120 引起病理性疼痛，而由这些药物引起的病理性疼痛的发展 脊髓背角神经胶质细胞激活的力学特性。我们假设NRTIs 通过神经胶质激活促进神经回路中的疼痛发病，而gp120和阿片类药物可以加重疼痛 这种情况。我们将通过执行以下操作来检验这一假设：(1)单细胞转录分析 NRTIs联合阿片类药物或gp120诱导的细胞神经病变(目标1)，(2)全细胞 斑贴记录用于表征阿片类药物或gp120引起的NRTI的病理性疼痛神经回路(目的 2)，以及(3)行为测试，以表征使用阿片类药物或gp120的NRTI引起的病理性疼痛(目标3)。 这项研究的结果将有助于确定CART对中枢神经系统及其 与艾滋病毒和阿片类药物的相互作用。

PROJECT SUMMARY Combination antiretroviral therapy (cART) is the current first-line treatment for human immunodeficiency virus (HIV) infection. Unfortunately, cART is implicated in various forms of HIV-associated neurological disorders. Pain is the most common neurological complication that significantly reduces the quality of life of many people living with HIV (PLWH), and emerging evidence suggests cART critically contributes to the development of pain in PLWH. However, the mechanism by which cART promotes pain pathogenesis is still incompletely understood and rationale-based effective adjuvant therapy is not available. In this project, we aim to elucidate the pathogenic mechanism of nucleoside reverse transcriptase inhibitors (NRTIs), which are the cornerstone antiretroviral drugs in cART regimens and induce neuropathic pain. Because PLWH on cART are commonly exposed to opioids and HIV-1 gp120 protein that causes pain, we will also investigate the potential pathogenic interaction between NRTIs and opioids or gp120. Our data show that separate administration of NRTIs, morphine, or gp120 to mice causes pathological pain, and that the development of pathological pain induced by these agents shares mechanistic properties with the activation of glial cells in the spinal dorsal horn. We hypothesize that NRTIs promote pain pathogenesis in the neural circuit via glial activation and that gp120 and opioids can exacerbate this condition. We will test this hypothesis by performing: (1) single cell transcriptomic analysis to characterize the cellular neuropathogenesis induced by NRTIs in conjunction with opioids or gp120 (Aim 1), (2) whole cell patch recording to characterize the pathologic pain neural circuitry induced by NRTIs with opioids or gp120 (Aim 2), and (3) behavioral testing to characterize pathological pain induced by NRTIs with opioids or gp120 (Aim 3). Results from this research will help to define the potential detrimental impact of cART on the CNS and its interactions with HIV and opioids.