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

摘要 人类免疫缺陷病毒-1（HIV）相关的神经性疼痛影响了3790万感染者中的55-67% 世界各地的个人。虽然抗逆转录病毒疗法成功地降低了艾滋病的流行率， 神经性疼痛继续影响许多HIV患者。治疗选择有限，而且往往 无效和不良副作用是常见的。更好的结果可以通过识别有利的 已经可用的或作为潜在的新镇痛剂出现的药物组合，或通过开发新的 更有效的药物。我们建议测试一种新的药理学联合治疗策略， 大麻的成分，β-carbellene（BCP，一种萜烯）和大麻二酚（CBD，一种次要的大麻素）， 有效地抑制HIV相关慢性神经性疼痛而没有副作用和/或滥用可能性。临床前 CBD在神经损伤疼痛模型中镇痛作用的剂量反应研究表明，尽管CBD具有 缓解慢性神经性疼痛状态的潜力，其显示出中等功效。然而，止痛剂 CBD的作用与僵住症无关，并且不会损害运动性能或产生镇静作用。 剂量范围很广有趣的是，BCP也显示出管理慢性疼痛的潜力，但它表现出 中等功效。此外，增加CBD的镇痛功效而不诱导潜在的 副作用或滥用的可能性。选择这种双CBD-BCP策略的理由是 基于其个体镇痛效果和安全性特征。目标1将检验以下假设： 对于单独的CBD，BCP和CBD组合将产生增强的镇痛作用（协同作用）， 改进的和临床相关的HIV慢性神经性疼痛模型。我们将评估多个结果指标 捕捉慢性疼痛的感觉和情感维度。等辐射线分析将证明 相互作用（例如协同作用）。目标2将筛选任何副作用，滥用潜力和发展 镇痛耐受 拟议的研究将通过提供一个有效的方法来显著影响HIV相关慢性疼痛管理领域。 新的联合疗法，CBD和BCP，比目前的疗法具有关键优势。它是安全的，有效的， 而且不会上瘾CBD和BCP的抗焦虑和抗抑郁作用对靶向 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，因为对抗这种流行病的关键策略之一（HEAL倡议）是通过改善疼痛 管理并举 非成瘾方法的发展 .天然产品BCP是由 美国食品和药物管理局（FDA）作为食品添加剂，以其良好的安全性而闻名。因此，我们认为， BCP与CBD联合治疗HIV相关的慢性神经性疼痛可能会导致快速缓解。 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.