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.

项目摘要抗逆转录病毒疗法（CART）是目前针对人类免疫缺陷病毒的一线治疗（HIV）感染。不幸的是，购物车与各种形式的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，大大降低了许多生活的人的生活质量与艾滋病毒（PLWH）和新兴证据一起表明，卡车对疼痛的发展有助于 plwh。然而，手推车促进疼痛发病机理的机制仍未完全理解基于基本原理的有效辅助疗法不可用。在这个项目中，我们旨在阐明致病性核苷逆转录酶抑制剂（NRTIS）的机理，它是基石抗逆转录病毒药物在购物车方案中诱发神经性疼痛。因为购物车上的PLWH通常暴露于阿片类药物中，并且引起疼痛的HIV-1 GP120蛋白，我们还将研究 NRTIS和阿片类药物或GP120。我们的数据表明，将NRTI，吗啡或GP120分开给小鼠施用引起病理疼痛，并且这些药物诱导的病理疼痛的发展机械特性，具有脊柱背角中神经胶质细胞的激活。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理，而GP120和阿片类药物会加剧这种情况。我们将通过执行：（1）单细胞转录组分析来检验此假设以表征 NRTI与阿片类药物或GP120诱导的细胞神经病发生（AIM 1），（2）全细胞贴片记录以表征由阿片类药物或GP120诱导的病理疼痛神经回路（AIM 2）和（3）行为测试以表征由阿片类药物或GP120诱导的病理疼痛（AIM 3）。这项研究的结果将有助于定义购物车对中枢神经系统及其ITS的潜在有害影响与艾滋病毒和阿片类药物的相互作用。