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

阿片类药物和 HIV 背景下 NRTI 诱导的疼痛发病机制的细胞和电路机制

• 批准号: 10559782
• 负责人: SHAO-JUN TANG
• 金额: $ 56.92万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559782
• 关键词: AIDS/HIV problem; Abbreviations; Ablation; Adjuvant Therapy; Anti-Retroviral Agents; Astrocytes; Behavior; Behavioral; Cell Nucleus; Cell physiology; Cells; Complication; Data; Development; Exposure to; Ganciclovir; Glial Fibrillary Acidic Protein; HIV; HIV Envelope Protein gp120; HIV-1; Highly Active Antiretroviral Therapy; Hyperalgesia; Integrase Inhibitors; Interleukin-1 beta; Knock-out; Knowledge; Lamivudine; Measures; Microglia; Mitochondria; Mitochondrial DNA; Morphine; Mus; Neuraxis; Neurologic; Neuropathogenesis; Nucleosides; Opioid; Pain; Pathogenesis; Pathogenicity; Pathologic; Pathway Analysis; Patients; Persons; Pharmaceutical Preparations; Process; Production; Property; Protease Inhibitor; Proteins; Quality of life; Reaction; Reactive Oxygen Species; Regimen; Research; Reverse Transcriptase Inhibitors; Role; SOD2 gene; Small Nuclear RNA; Spinal; Spinal Cord; Synapses; Synaptic plasticity; Syndrome; TNF gene; Tenofovir; Testing; Toxic effect; Toxin; Transgenic Mice; Transgenic Organisms; Virus Diseases; Virus Replication; Zalcitabine; Zidovudine; allodynia; antiretroviral therapy; base; behavior test; conditional knockout; dorsal horn; emtricitabine; experimental study; glial activation; insight; neural circuit; neuroAIDS; neuroinflammation; non-nucleoside reverse transcriptase inhibitors; opioid use; opioid use disorder; overexpression; pain behavior; pain sensation; painful neuropathy; postsynaptic; single-cell RNA sequencing; transcriptome sequencing; transcriptomics; transmission process; viral transmission

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.

项目摘要 联合抗逆转录病毒治疗（cART）是目前人类免疫缺陷病毒的一线治疗方法 (HIV)感染不幸的是，cART与各种形式的HIV相关神经系统疾病有关。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， 艾滋病毒感染者（PLWH），新的证据表明，cART对疼痛的发展有重要作用， PLWH。然而，cART促进疼痛发病的机制仍不完全清楚 并且基于合理的有效辅助治疗不可用。在这个项目中，我们的目标是阐明致病性 核苷类逆转录酶抑制剂（NRTI）是抗逆转录病毒药物的基石， 并诱导神经性疼痛。由于接受cART治疗的PLWH通常暴露于阿片类药物， HIV-1 gp 120蛋白引起疼痛，我们也将研究潜在的致病性之间的相互作用， NRTI和阿片类药物或gp 120。我们的数据表明，分别给予小鼠NRTI、吗啡或gp 120， 导致病理性疼痛，并且由这些药物诱导的病理性疼痛的发展 机械特性与脊髓背角胶质细胞的激活有关。我们假设NRTI 通过神经胶质激活促进神经回路中的疼痛发病机制，并且GP 120和阿片类药物可加剧 这个条件。我们将通过以下方法检验这一假设：（1）单细胞转录组学分析， NRTI与阿片类药物或gp 120联合诱导的细胞神经病理学（目的1），（2）全细胞 斑片记录来表征阿片类或gp 120的NRTI诱导的病理性疼痛神经回路（Aim 2）和（3）行为测试，以表征NRTI与阿片类药物或gp 120诱导的病理性疼痛（目的3）。 这项研究的结果将有助于确定cART对CNS的潜在有害影响及其可能的副作用。 与艾滋病毒和阿片类药物的相互作用。