Beta-caryophyllene (BCP) and cannabidiol (CBD) combination: HIV-1 chronic neuropathic pain

摘要 在3790万感染者中，与人类免疫缺陷病毒-1(HIV)相关的神经病理性疼痛影响55%至67% 世界各地的个人。虽然抗逆转录病毒疗法已经成功地降低了艾滋病的流行， 神经性疼痛继续影响着许多艾滋病毒携带者。治疗选择有限，而且往往 效果不佳，副作用很常见。通过确定有利的条件，可能会取得更好的结果 已有的或作为潜在的新镇痛剂或通过开发新的止痛药而出现的药物的组合 以及更有效的药物。我们建议测试一种新的药物联合治疗策略，包括 大麻、β-石竹烯(ΒCP，一种萜类)和大麻二酚(CBD，一种次要的大麻类化合物)的成分，至 有效抑制艾滋病毒相关的慢性神经性疼痛，没有副作用和/或滥用潜力。临床前研究 在神经损伤疼痛模型中对CBD镇痛作用的剂量-反应研究表明，尽管CBD有 有缓解慢性神经病理性疼痛状态的潜力，它显示出中等的疗效。然而，止痛药 CBD的效果与眩晕无关，也不会损害运动能力或产生镇静作用。 剂量范围很广。有趣的是，BCP在治疗慢性疼痛方面也显示出潜力，但它表现出 疗效中等。此外，增加CBD的止痛效果而不诱导潜力的策略 迫切需要副作用或滥用的可能性。选择这种双重CBD-ΒCP策略的理由是 基于其个别的止痛效果和安全性。目标1将检验假设，在比较中 单独使用CBD，BCP和CBD联合使用将产生增强的止痛效果(协同作用)。 改进的和临床相关的HIV慢性神经病理性疼痛模型。我们将评估多种结果衡量标准 捕捉慢性疼痛的感觉和情感维度。等高线分析将证明其性质 交互作用(例如，协同作用)。目标2将筛查任何副作用，滥用潜力和发展 止痛耐受性。 拟议的研究将通过提供一种与艾滋病毒相关的慢性疼痛管理领域的 新的联合疗法，CBD和BCP，与现有疗法相比具有关键优势。它是安全有效的， 而且不会上瘾。CBD和BCP的抗焦虑和抗抑郁作用对靶点有额外的好处 慢性疼痛合并症。此外，这种联合治疗将对阿片类药物产生重大影响 流行病，因为抗击这种流行病的关键战略之一(治愈倡议)是通过改善疼痛 管理人 非成瘾方法的发展 。天然产物BCP经美国食品和药物管理局批准 食品和药物管理局(FDA)作为一种食品添加剂，以其良好的安全性而闻名。因此， BCP联合CBD治疗HIV相关的慢性神经病理性疼痛可导致快速的 翻译给病人。

ABSTRACT Human Immunodeficiency Virus-1 (HIV)-related neuropathic pain affects 55-67% of the 37.9 million infected individuals worldwide. Although antiretroviral therapy has successfully reduced the prevalence of AIDS, neuropathic pain continues to affect many individuals with HIV. Treatment options are limited and often ineffective, and adverse side effects are common. Better outcomes may be achieved by identifying favorable combinations of drugs that are already available or emerging as potential new analgesics or by developing new and more effective drugs. We propose to test a novel pharmacological combination therapeutic strategy involving constituents of cannabis, Beta-caryophyllene (ΒCP, a terpene), and cannabidiol (CBD, a minor cannabinoid), to effectively inhibit HIV-related chronic neuropathic pain without side effects and/or abuse potential. A preclinical dose-response study of the analgesic effect of CBD in a nerve-injury pain model showed that, although CBD has the potential to alleviate a chronic neuropathic pain state, it showed moderate efficacy. However, the analgesic effect of CBD was not associated with catalepsy, and did not impair motor performance or produce sedation over a wide range of doses. Interestingly, BCP also showed potential in managing chronic pain, but it exhibited moderate efficacy. Furthermore, a strategy to increase the analgesic efficacy of CBD without inducing potential side effects or abuse potential is urgently needed. The rationale for choosing this dual CBD-ΒCP strategy is based on its individual analgesic effects and safety profiles. Aim 1 will test the hypothesis that in comparison with CBD alone, BCP and CBD in combination will produce an enhanced analgesic effect (synergistic) in an improved and clinically relevant HIV chronic neuropathic pain model. We will assess multiple outcome measures capturing sensory and affective dimensions of chronic pain. Isobolographic analysis will demonstrate the nature of interaction (e.g. synergistic). Aim 2 will screen for any side effects, abuse potential and development of analgesic tolerance. The proposed studies will significantly impact the field of HIV-related chronic pain management by providing a new combination therapy, CBD and BCP, that has critical advantages over current therapies. It is safe, effective, and non-addictive. The anxiolytic and anti-depressive effects of CBD and BCP are of additional benefit to target chronic pain comorbidities. Furthermore, this combination therapy will have a significant impact on the opioid epidemic, because one of the key strategies to combat this epidemic (HEAL initiative) is through improved pain management by the development of non-addictive approaches . The natural product, BCP, is approved by the Food and Drug Administration (FDA) as a food additive, known for its favorable safety profile. Therefore, combination of the BCP with CBD for the treatment of HIV-related chronic neuropathic pain could lead to a rapid translation to patients.