Endocannabinoid system and HIV-related neuropathic pain

项目摘要/摘要 与人类免疫缺陷病毒-1(HIV)相关的慢性神经性疼痛影响到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)有能力限制 从艾滋病毒到艾滋病的进展，艾滋病毒阳性者继续经历神经病理性疼痛。治疗方案 是有限的，往往是无效的，而且不良副作用很常见。尽管治疗用途(自我用药) 除了对大麻可能的药用用途感兴趣外，艾滋病毒感染者对大麻的需求也在增长， 特别是在疼痛治疗方面，到目前为止，还没有关于内源性大麻系统是否以及如何使用的数据 (ECB)是调控HIV相关的慢性神经病理性疼痛。例如，欧洲央行系统是否正常运行， 在控制神经病理性疼痛方面有效，还是在艾滋病毒相关神经病理性疼痛的背景下受损？此外， 在这种情况下，暴露于大麻类物质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一知识差距，以提供关键的 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， 欧洲央行系统在治疗艾滋病毒相关的慢性神经病理性疼痛方面仍然有效和有效。为了测试这一点 假设一种综合的多学科方法，包括行为、药理学、分子 将使用生物学、生物化学和液-色质谱联用分析。我们将使用HIV 转基因大鼠(HIV-TG)神经病变模型，模拟ART时代的HIV慢性状态。目标1将 执行第一次临床前研究以表征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 神经病态模型。将对欧洲央行系统的组成部分进行基因和蛋白质表达分析 模式、信号、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)临床相关的具有不同药理特征的大麻素激动剂) HIV-TG模型中的神经病理性疼痛行为和ECB。我们将使用感官的行为评估 并在HIV-TG中测试疼痛的厌恶性质，以测试这些大麻类化合物的止痛效果。此外，我们还将 还要监测大麻素的副作用。 拟议的研究将大大推进艾滋病毒慢性疼痛管理和大麻类药物领域的发展。 ART时代通过提供关键和基本的新知识来了解欧洲央行系统在艾滋病毒相关领域的地位 慢性神经病理性疼痛。欧洲央行系统在这种HIV慢性疾病中起作用和有效的新概念 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 在艾滋病相关的慢性神经病理性疼痛的艺术时代。

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.