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

β-石竹烯 (BCP) 和大麻二酚 (CBD) 组合：HIV-1 慢性神经性疼痛

• 批准号: 10490249
• 负责人: Khalid Benamar
• 金额: $ 1.16万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490249
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Affective; Analgesics; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Area; Attention; Behavior; Beta-caryophyllene; Cannabidiol; Cannabinoids; Cannabis; Cannabis sativa plant; Caring; Catalepsy; Chronic; Combined Modality Therapy; Data; Dependence; Development; Dimensions; Dose; Drug Combinations; Epidemic; Exhibits; Family; Feeling; Female; Food Additives; Goals; HIV; HIV Seropositivity; HIV-1; Health; Helping to End Addiction Long-term; Herb; Hypersensitivity; Individual; Lead; Link; Medical; Mental Depression; Minor; Modeling; National Institute of Drug Abuse; Natural Products; Nature; Needles; Neurologic; Numbness; Opioid; Outcome; Outcome Measure; Pain; Pain management; Patients; Performance; Persistent pain; Persons; Pharmaceutical Preparations; Pharmacology; Plants; Prevalence; Proteins; Quality of life; Rattus; Research; Role; Safety; Sedation procedure; Sensory; Shock; Shoes; Sleep Deprivation; Terpenes; Testing; Therapeutic; Therapeutic Agents; Touch sensation; Transgenic Organisms; Translations; United States Food and Drug Administration; Virus Diseases; abuse liability; antiretroviral therapy; base; chronic neuropathic pain; chronic pain; chronic pain management; clinically relevant; combat; comorbidity; depressive symptoms; effective therapy; experience; improved; innovation; male; mechanical allodynia; nerve injury; new combination therapies; novel; opioid epidemic; pain model; pain reduction; painful neuropathy; phytocannabinoid; pre-clinical; response; side effect

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.

抽象的 人类免疫缺陷病毒 1 (HIV) 相关的神经性疼痛影响着 3790 万名感染者中的 55-67% 世界各地的个人。尽管抗逆转录病毒治疗已成功降低艾滋病的患病率， 神经性疼痛继续影响许多艾滋病毒感染者。治疗选择有限且经常 效果不佳，而且不良副作用也很常见。通过识别有利的因素可以取得更好的结果 已经可用或作为潜在新镇痛剂出现的药物组合，或通过开发新药物 和更有效的药物。我们建议测试一种新的药理学联合治疗策略，涉及 大麻、β-石竹烯（βCP，一种萜烯）和大麻二酚（CBD，一种次要大麻素）的成分， 有效抑制与艾滋病毒相关的慢性神经性疼痛，无副作用和/或滥用潜力。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，它显示出中等功效。然而镇痛药 CBD 的作用与僵直症无关，并且不会损害运动能力或产生镇静作用 剂量范围广。有趣的是，BCP 也显示出治疗慢性疼痛的潜力，但它表现出 功效中等。此外，在不诱发潜在风险的情况下提高 CBD 镇痛功效的策略 副作用或滥用可能性是迫切需要的。选择这种双重 CBD-BCP 策略的理由是 基于其各自的镇痛效果和安全性。目标 1 将检验以下假设： 单独使用 CBD，BCP 和 CBD 组合将产生增强的镇痛效果（协同） 改进的和临床相关的艾滋病毒慢性神经性疼痛模型。我们将评估多种结果指标 捕捉慢性疼痛的感觉和情感维度。等辐射线分析将证明性质 相互作用（例如协同作用）。目标 2 将筛查任何副作用、滥用潜力和发展 镇痛耐受性。 拟议的研究将通过提供一种方法来显着影响与艾滋病毒相关的慢性疼痛管理领域。 新的联合疗法 CBD 和 BCP 比现有疗法具有关键优势。它安全、有效、 并且不会上瘾。 CBD 和 BCP 的抗焦虑和抗抑郁作用对目标有额外的好处 慢性疼痛合并症。此外，这种联合疗法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 举措）是通过改善疼痛 管理由 开发非成瘾方法 。天然产物 BCP 已获得 FDA 批准 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。所以， 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 翻译给患者。