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.

项目概要/摘要 人类免疫缺陷病毒 1 (HIV) 相关的慢性神经性疼痛影响着 38 名患者中的大多数 (55-67%) 全球有 100 万感染者。尽管目前的抗逆转录病毒疗法（ART）能够限制 随着艾滋病毒发展为艾滋病，艾滋病毒阳性者继续经历神经性疼痛。治疗方案 效果有限，通常无效，而且不良副作用也很常见。虽然治疗用途（自我药疗） 除了对大麻可能的药用用途的兴趣外，艾滋病毒感染者对大麻的使用也在增加， 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是否以及如何作用的数据 (eCB) 在 HIV 相关的慢性神经性疼痛中受到调节。例如，eCB 系统是否正常运行？ 能有效控制神经性疼痛，还是在 HIV 相关神经性疼痛的情况下受损？而且， 在这种情况下，接触大麻素是否以及如何影响 eCB 系统的组件是 仍然未知。该 CEBRA 研究项目旨在解决这一知识差距，以提供关键的 ART 时代 eCB 和 HIV 研究领域的方向。我们的中心假设是，在 ART 时代， eCB 系统在与 HIV 相关的慢性神经性疼痛中保持功能和有效。为了测试这个 假设是一种综合的多学科方法，包括行为学、药理学、分子学 将使用生物学、生物化学和液相色谱质谱分析。我们将利用艾滋病毒 转基因大鼠（HIV-tg）神经病变模型，模拟 ART 时代的 HIV 慢性病。目标1将 进行第一个临床前研究来表征 eCB 系统的状态（例如内源配体、 HIV-tg 中参与疼痛控制的关键区域中涉及 eCB 代谢的酶和 CB 受体） 神经病模型。将分析 eCB 系统组件的基因和蛋白质表达 模式、信号传导、内源性大麻素水平和/或酶活性。目标2将决定效果 （急性和慢性）具有不同药理学特征的临床相关大麻素激动剂） HIV-tg 模型中的神经性疼痛样行为和 eCB。我们将使用感官行为评估 和 HIV-tg 中疼痛的厌恶性质，以测试这些大麻素的镇痛效果。此外，我们将 还监测大麻素的副作用。 拟议的研究将显着推进艾滋病毒慢性疼痛管理和大麻素领域 通过提供有关 ECB 系统在 HIV 相关领域的状况的重要且基本的新知识，引领 ART 时代的到来 慢性神经性疼痛。 eCB 系统在这种 HIV 慢性病中发挥作用且有效的新概念 这种情况将为基于大麻素的机制和策略的临床相关研究铺平道路 ART 时代与 HIV 相关的慢性神经性疼痛。