Endocannabinoid system and HIV-related neuropathic pain

内源性大麻素系统和 HIV 相关的神经性疼痛

• 批准号: 10852472
• 负责人: Khalid Benamar
• 金额: $ 50.12万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10852472
• 关键词: Endocannabinoid; system; HIV; related; neuropathic

PROJECT SUMMARY/ABSTRACT Human Immunodeficiency Virus-1 (HIV)-related chronic neuropathic pain affects a majority (55-67%) of the 38 million infected individuals worldwide. Despite the ability of current anti-retroviral therapy (ART) to limit the progression of HIV to AIDS, HIV-positive individuals continue to experience neuropathic pain. Treatment options are limited, often ineffective, and adverse side effects are common. Although therapeutic use (self-medication) of cannabis by HIV-infected people is growing in addition to an interest in the possible medicinal use of cannabis, particularly for pain management, to date, there are no data on whether and how the endocannabinoid system (eCB) is regulated in the HIV-related chronic neuropathic pain. For example, is eCB system functional and effective in controlling neuropathic pain, or impaired in the context of HIV-related neuropathic pain? Moreover, whether and how the exposure to cannabinoids affects the components of the eCB system in this condition is still unknown. This CEBRA research project is designed to address this knowledge gap to provide critical directions for the field of eCB and HIV research in the ART era. Our central hypothesis is that in the ART era, the eCB system remains functional and effective in HIV-related chronic neuropathic pain. To test this hypothesis a comprehensive multidisciplinary approach including behavioral, pharmacological, molecular biology, biochemistry, and Liquid Chromatograph Mass Spectrometry assays will be used. We will use the HIV transgenic rats (HIV-tg) neuropathic model that mimics the HIV chronic condition in the ART era. Aim 1 will perform the first preclinical studies to characterize the status of the eCB system (e.g., endogenous ligands, enzymes involved in eCB metabolism, and CB receptors) in the key areas involved in pain control in the HIV-tg neuropathic model. The components of the eCB system will be analyzed for gene and proteins expression patterns, signaling, levels of endogenous cannabinoids and/or activity enzymatic. Aim 2 will determine the effect (acute and chronic) of clinically relevant cannabinoid agonists with different pharmacological profiles) on neuropathic pain-like behaviors and eCBs in the HIV-tg model. We will use behavioral assessments of sensory and aversive qualities of pain in HIV-tg to test the analgesic effects of these cannabinoids. Additionally, we will also monitor for cannabinoid side effects. The proposed studies will significantly advance the fields of HIV chronic pain management and cannabinoids in the ART era by providing a critical and fundamental new knowledge of the eCB system status in HIV-related chronic neuropathic pain. The novel concept that eCB system is functional and effective in this HIV chronic condition would pave the way for clinically relevant research on cannabinoid-based mechanisms and strategies in HIV-related chronic neuropathic pain in the ART era.

项目摘要/摘要 人类免疫缺陷病毒1（HIV）相关的慢性神经性疼痛影响38的大部分（55-67％） 全球有百万感染的人。尽管目前的抗逆转录病毒疗法（ART）有能力限制 艾滋病毒向艾滋病的发展，艾滋病毒阳性个体继续经历神经性疼痛。治疗选择 有限，通常无效，不良副作用很常见。虽然使用治疗（自我药物） 艾滋病毒感染者大麻的大麻除了对大麻的可能使用大麻的兴趣之外，还在增长 特别是对于疼痛管理，迄今为止，还没有关于内源性大麻素系统的数据 （欧洲央行）在与HIV相关的慢性神经性疼痛中受到调节。例如，欧洲央行系统功能性和 有效控制神经性疼痛，还是在与HIV相关的神经性疼痛的背景下受损？而且， 在这种情况下，对大麻素的暴露是否以及如何影响欧洲央行系统的组成部分 仍然未知。该CEBRA研究项目旨在解决这个知识差距，以提供关键 艺术时代欧洲央行和艾滋病毒研究领域的方向。我们的中心假设是在艺术时代， 欧洲央行系统在与HIV相关的慢性神经性疼痛中保持功能和有效。测试这个 假设一种全面的多学科方法，包括行为，药理，分子 将使用生物学，生物化学和液相色谱质谱法测定法。我们将使用艾滋病毒 转基因大鼠（HIV-TG）神经性模型，模仿艺术时代的HIV慢性病。目标1意志 执行第一个临床前研究以表征欧洲央行系统的状态（例如，内源配体， 涉及欧洲央行代谢和CB受体的酶）在HIV-TG中涉及的关键区域 神经性模型。将分析欧洲央行系统的组成部分的基因和蛋白质表达 模式，信号传导，内源性大麻素和/或活性酶促的水平。 AIM 2将决定效果 （急性和慢性）具有不同药理特征的临床相关大麻素激动剂） HIV-TG模型中的神经性疼痛行为和ECB。我们将使用感官的行为评估 HIV-TG中疼痛的厌恶质量以测试这些大麻素的镇痛作用。此外，我们会的 还监测大麻素的副作用。 拟议的研究将显着推进HIV慢性疼痛管理和大麻素的领域 艺术时代通过提供与HIV相关的欧洲央行系统状况的关键和基本的新知识 慢性神经性疼痛。欧洲央行系统在此HIV慢性中具有功能有效的新颖概念 条件将为基于大麻素机制和策略的临床相关研究铺平道路 在艺术时代与HIV相关的慢性神经性疼痛。