Cooperative mechanisms of HIV and opiods in pain pathogenisis

HIV和阿片类药物在疼痛发病机制中的合作机制

基本信息

批准号：
10665625
负责人：
JIN M CHUNG
金额：
$ 59.49万
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：
2021
资助国家：
美国
起止时间：
2021-10-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10665625
关键词：
Acquired Immunodeficiency Syndrome Analgesics Astrocytes Behavioral Biopsy CASP1 gene Caspase Cells Chronic Clinical Clinical Data Collaborations Electrophysiology (science)Goals HIV HIV Envelope Protein gp120 HIV-1 HIV/AIDS Human Hyperalgesia Inflammasome Inflammation Mediators Inflammatory Interleukin-1 beta MMP2 gene Matrix Metalloproteinases Mediating Modeling Molecular Molecular Analysis Morphine Mutation Opioid Pain Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Posterior Horn Cells Protein Analysis Proteins Research Role Spinal cord posterior horn Testing Up-Regulation Work behavior test central sensitization conditional knockout design dosage improved interdisciplinary approach mechanical allodynia morphine administration mouse model mutant neuroinflammation neuropathology opioid epidemic opioid overdose painful neuropathy patch clamp prevent receptor side effect spontaneous pain synergism therapeutically effective transcriptome

项目摘要

ABSTRACT Opioid-based analgesics are commonly used for temporal relief of severe pain in HIV-1/AIDS patients. However, recent clinical data show that chronic opioid treatment causes a heightened pain state (hyperalgesia). This debilitating side effect requires escalating dosages of the analgesics in order to be effective, and thus may directly contribute to opioid overdose and epidemics. To prevent this clinically important side effect, it is necessary to understand how chronic use of opioids causes hyperalgesia in HIV patients. In the HIV-1 gp120 mouse model that recapitulates extensive pain-related pathologies of HIV human patients, we simulate morphine exacerbation of gp120-induced pain. The goal of this project is to elucidate the pathogenic mechanism by which morphine potentiates HIV-associated pain. Our prior work reveals that neuroinflammation in the spinal cord dorsal horn (SDH) is a cardinal neuropathology in HIV patients with neuropathic pain. Based on our preliminary studies, we propose that neuroinflammation is a convergent neuropathological mechanism by which gp120 and opioids cooperate to potentiate pathological pain. Our preliminary studies further show that gp120 and morphine elicit neuroinflammation via overlapped but distinct molecular pathways. We hypothesize that morphine and gp120 synergize pain pathogenesis by co-activating the neuroinflammatory pathways. The proposed research is to test this central hypothesis by elucidating the roles of these pathways in pain pathogenesis induced by gp120 and morphine alone or in combination. We will use interdisciplinary approaches of protein analysis, single cell transcriptome analysis, whole cell patch recording and behavioral testing. Results from these studies will significantly improve our understanding of the mechanism by which morphine exacerbates HIV-associated pain.

抽象的基于阿片类药物的镇痛药通常用于暂时缓解HIV-1/艾滋病患者的严重疼痛。但是，最近的临床数据表明，慢性阿片类药物治疗会导致疼痛状态升高（痛风）。这种使人衰弱的副作用需要不断升级的止痛药才能有效，因此可能直接导致阿片类药物过量和流行病。在临床上预防这一重要的副作用，有必要了解长期使用阿片类药物如何引起艾滋病毒的痛风患者。在HIV-1 GP120小鼠模型中，该模型概括了HIV人类的广泛疼痛病理患者，我们模拟了GP120诱导的疼痛的吗啡加剧。该项目的目的是阐明吗啡会增强HIV相关疼痛的致病机制。我们先前的工作表明脊髓背角（SDH）中的神经炎症是HIV患者的基本神经病理学神经性疼痛。根据我们的初步研究，我们建议神经炎症是一种收敛性 GP120和阿片类药物合作以增强病理疼痛的神经病理机制。我们的初步研究进一步表明，GP120和吗啡通过重叠但独特的神经炎症引起神经炎症分子途径。我们假设吗啡和GP120通过共激活来协同疼痛发病机理神经炎症途径。拟议的研究是通过阐明这些途径在GP120和吗啡诱导的疼痛发病机理中的作用或组合。我们将使用蛋白质分析的跨学科方法，单细胞转录组分析，全细胞斑块记录和行为测试。这些研究的结果将显着提高我们对吗啡加剧与HIV相关的疼痛的机制。