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.

项目总结/摘要 人类免疫缺陷病毒-1（HIV）相关的慢性神经性疼痛影响了38例中的大多数（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HIV进展为AIDS，HIV阳性个体继续经历神经性疼痛。治疗选择 是有限的，往往无效，不良副作用是常见的。自我药疗（self-medicine） 除了对大麻可能的药用感兴趣外， 特别是对于疼痛管理，到目前为止，还没有关于内源性大麻素系统是否以及如何 (eCB)在HIV相关的慢性神经病理性疼痛中受到调节。例如，eCB系统是否正常工作， 有效控制神经性疼痛，或在HIV相关神经性疼痛的背景下受损？此外，委员会认为， 在这种情况下，大麻素的暴露是否以及如何影响eCB系统的成分， 仍然未知。这个CEBRA研究项目旨在解决这一知识差距， 为ART时代的eCB和HIV研究领域指明了方向。我们的中心假设是，在ART时代， eCB系统在HIV相关的慢性神经性疼痛中保持功能和有效。为了验证这一 假设一个全面的多学科方法，包括行为，药理学，分子 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）神经病模型，其模拟ART时代的HIV慢性病症。目标1将 进行第一项临床前研究，以表征eCB系统的状态（例如，内源性配体， 参与eCB代谢的酶和CB受体）在HIV-tg中参与疼痛控制的关键区域 神经病理模型将分析eCB系统组件的基因和蛋白表达 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。我们将使用行为评估的感官 以及HIV-tg中疼痛的厌恶性质，以测试这些大麻素的镇痛作用。此外，我们将 同时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， 通过提供关于艾滋病毒相关的eCB系统状态的关键和基本的新知识， 慢性神经性疼痛新的概念，eCB系统是功能和有效的，在这种艾滋病毒慢性 条件将为基于大麻素的机制和策略的临床相关研究铺平道路 艾滋病相关的慢性神经性疼痛。