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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.

摘要阿片类止痛药通常用于暂时缓解HIV-1/AIDS患者的剧烈疼痛。然而，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加剧。 (痛觉过敏)。这种使人衰弱的副作用需要增加镇痛剂的剂量才能有效，因此可能直接导致阿片类药物过量和流行。从临床上防止这种情况发生重要的副作用，有必要了解长期使用阿片类药物是如何导致艾滋病毒的痛敏的病人。在HIV-1gp120小鼠模型中，该模型概括了HIV人类广泛的疼痛相关病理患者，我们模拟吗啡加重gp120诱导的疼痛。这个项目的目标是阐明吗啡加重HIV相关疼痛的致病机制。我们之前的工作表明脊髓背角(SDH)神经炎是HIV患者的主要神经病理改变神经性疼痛。根据我们的初步研究，我们认为神经炎症是一种汇聚性的 Gp120和阿片类药物协同增强病理性疼痛的神经病理机制。我们的初步研究进一步表明，gp120和吗啡通过重叠但不同的方式引起神经炎症。分子途径。我们假设吗啡和gp120通过共同激活而协同作用于疼痛发病机制。神经炎性通路。这项拟议的研究旨在通过阐明这些通路在gp120和吗啡单独或联合诱导的疼痛发病机制中的作用。我们会使用蛋白质分析、单细胞转录组分析、全细胞斑块等跨学科方法录音和行为测试。这些研究的结果将极大地提高我们对吗啡加重HIV相关疼痛的机制。