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

基本信息

批准号：
10704142
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
项目类别：
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/10704142
关键词：
Abbreviations Ablation Adjuvant Therapy Anti-Retroviral Agents Astrocytes Behavior Behavioral Cell physiology Cells Central Nervous System Complication Data Development Exposure to Ganciclovir Glial Fibrillary Acidic Protein HIV HIV Envelope Protein gp120 HIV-1 HIV/AIDS Highly Active Antiretroviral Therapy Hyperalgesia Integrase Inhibitors Interleukin-1 beta Knock-out Knowledge Lamivudine Measures Microglia Mitochondria Mitochondrial DNA Morphine Mus 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 Spinal Spinal Cord Synapses Synaptic plasticity Syndrome TNF gene Tenofovir Testing Toxic effect Toxin Transgenic Mice Transgenic Organisms Vertebral column Virus Diseases Virus Replication Zalcitabine Zidovudine allodynia antiretroviral therapy 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 nucleus RNA-sequencing single-cell RNA sequencing transcriptomics transmission process viral transmission

项目摘要

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.

项目概要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（艾滋病毒）感染。不幸的是，cART 与多种形式的 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，显着降低了许多人的生活质量 HIV 感染者 (PLWH) 患者，新出现的证据表明，cART 对艾滋病毒感染者 (PLWH) 患者疼痛的发生至关重要感染者。然而，cART促进疼痛发病机制仍不完全清楚并且尚无基于理论依据的有效辅助治疗。在这个项目中，我们的目标是阐明致病菌核苷逆转录酶抑制剂（NRTI）的机制，它是抗逆转录病毒药物的基石在 cART 方案中并诱发神经性疼痛。因为接受 cART 治疗的感染者通常会接触阿片类药物，并且 HIV-1 gp120 蛋白引起疼痛，我们还将研究两者之间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，对小鼠单独施用 NRTI、吗啡或 gp120 引起病理性疼痛，并且这些药物引起的病理性疼痛的发展具有共同特征脊髓背角神经胶质细胞激活的机制特性。我们假设 NRTI 通过神经胶质细胞激活促进神经回路中的疼痛发病机制，并且 gp120 和阿片类药物会加剧疼痛这个条件。我们将通过执行以下操作来检验这一假设：（1）单细胞转录组分析来表征 NRTI 与阿片类药物或 gp120 联合诱导的细胞神经病变（目标 1），(2) 全细胞贴片记录，用于表征 NRTI 与阿片类药物或 gp120 诱导的病理性疼痛神经回路（目的 2) 和 (3) 行为测试，以表征 NRTI 与阿片类药物或 gp120 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神经系统的潜在有害影响与艾滋病毒和阿片类药物的相互作用。