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

• 批准号: 10461002
• 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
• 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/10461002
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Analgesics; Astrocytes; Behavioral; Biopsy; CASP1 gene; Cells; Chronic; Clinical; Clinical Data; Collaborations; Electrophysiology (science); Goals; HIV; HIV Envelope Protein gp120; HIV-1; Human; Hyperalgesia; Inflammasome; Inflammation Mediators; Interleukin-1 beta; Lead; MMP2 gene; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Analysis; Morphine; Mutation; Neuropathy; 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; base; 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

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 阿片类镇痛药通常用于暂时缓解HIV-1/AIDS患者的严重疼痛。 然而，最近的临床数据显示，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逐渐增加止痛剂的剂量，以便 因此，可能直接导致阿片类药物过量和流行病。为了在临床上预防这种情况 重要的副作用，有必要了解阿片类药物的长期使用如何导致艾滋病毒的痛觉过敏 患者在HIV-1 gp 120小鼠模型中，该模型再现了HIV人类感染者的广泛疼痛相关病理学， 患者，我们模拟吗啡加剧的gp 120诱导的疼痛。这个项目的目标是阐明 吗啡增强HIV相关疼痛的致病机制。我们之前的研究表明， 脊髓背角（SDH）的神经炎症是HIV患者的主要神经病理学， 神经性疼痛基于我们的初步研究，我们提出神经炎症是一个收敛的， gp 120和阿片样物质协同作用以增强病理性疼痛的神经病理学机制。我们 初步研究进一步表明，GP 120和吗啡通过重叠但不同的途径引起神经炎症。 分子途径我们推测吗啡和gp 120通过共同激活神经元， 神经炎症通路拟议的研究是通过阐明 这些通路在由GP 120和吗啡单独或联合诱导的疼痛发病机制中的作用。我们将 使用跨学科的蛋白质分析方法，单细胞转录组分析，全细胞贴片 记录和行为测试。这些研究的结果将大大提高我们对 吗啡加剧艾滋病相关疼痛的机制。