Analgesic efficacy of single and combined minor cannabinoids and terpenes

单一和组合次要大麻素和萜烯的镇痛功效

• 批准号: 10231167
• 负责人: Sara J Ward
• 金额: $ 39.63万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231167
• 关键词: Absence of pain sensation; Acetic Acids; Achievement; Acids; Acute; Acute Pain; Agonist; Analgesics; Animal Model; Anti-Inflammatory Agents; Attenuated; Behavior; Beta-caryophyllene; Biological; Biological Assay; C57BL/6 Mouse; CNR2 gene; Cannabidiol; Cannabinoids; Cannabis; Cannabis sativa plant; Clinical; Combined Modality Therapy; Data; Dental Models; Dental Pulp; Dental Pulp Exposure; Development; Dose; Ensure; Face; Farming environment; Female; Follow-Up Studies; Goals; Hemp; Inflammation; Inflammatory; Investigation; Laboratories; Legal; Length; Literature; Measures; Mechanics; Medical Marijuana; Minor; Molecular; Morphine; Mus; Neuropathy; Nociception; Paclitaxel; Pain; Pain Measurement; Pain Research; Pain management; Pharmacology; Plants; Property; Rattus; Reporting; Research; Rodent Model; Sales; Sesquiterpenes; Sprague-Dawley Rats; Stretching; Tactile; Terpenes; Testing; Tetrahydrocannabinol; Therapeutic; Toothache; Visceral; Visceral pain; allodynia; behavior test; cannabigerol; chemotherapy; chronic pain; conditioned place preference; experimental study; interest; male; mechanical allodynia; mouse model; optimal treatments; orofacial; painful neuropathy; phytocannabinoid; pre-clinical; prevent; protective effect; response; translational medicine; treatment strategy

The primary goal of the proposed research is to empirically and quantitatively test the hypothesis that combinations of four biologically active components of Cannabis sativa act synergistically to protect against the development of pain in two rodent models: chemotherapy-induced neuropathic pain and pain associated with dental pulp exposure. In addition, effects of these Cannabis components on morphine analgesia and will also be assessed. Cannabis contains over 100 phytocannabinoids as well as several terpene compounds which are also biologically active. As stated in RFT-AT-19-008, while a growing body of literature suggests that Cannabis may have analgesic properties, the psychoactive effects of the phytocannabinoid ∆9-tetrahydrocannabinol (THC) limit its utility, calling for an investigation into the therapeutic potential of additional phytocannabinoids and terpenes found in the plant. Our laboratory has been studying the anti-neuropathic efficacy of the non- psychoactive phytocannabinoid cannabidiol (CBD) for over a decade. In addition to CBD, the minor cannabinoid cannabigerol (CBG), the acid form of THC THCA, and the terpene beta-caryophyllene (β-CP), are receiving increasing interest by clinicians as analgesics and/or anti-inflammatory agents. We have also recently demonstrated that β-CP prevents the development of mechanical sensitivity in a rat model of dental pain. Importantly, so-called “entourage effects” of Cannabis constituents are anecdotally discussed at length, but empirical data are woefully lacking, including the potential for synergistic interactions outside of THC. We determined that CBD acts synergistically with THC to attenuate mechanical allodynia associated with paclitaxel administration, while attenuating the antinociceptive effects of morphine on thermal sensitivity. Testing for such interactive effects requires rigorous dose response testing and analysis across single and combined agents, and these requirements increase with the number of agents to be combined. Animal modeling to test unique interactive effects of several Cannabis constituents provides a uniquely effective contribution to translational medicine, as executing such studies in a clinical setting is immensely more challenging and expensive. In the current proposal we will determine the efficacy of CBD, CBG, THCA, and β-CP alone and in combination on tactile allodynia and other pain-related behaviors in males and females. We will also determine the interactive effects of CBD, CBG, THCA, and β-CP with morphine on acute antinociceptive and visceral pain. At the completion of behavioral testing, complementary cellular and molecular approaches will be utilized to also characterize effects of single and combined agents on markers of pain and inflammation. The assembled team has the expertise and collaborative relationship to ensure the feasibility and achievement of the proposed project. The overall impact of the project will be to provide empirically-derived evidence for key components of Cannabis representing non-psychoactive single and/or combined for the treatment of acute and chronic pain.

拟议研究的主要目标是从经验和数量上检验以下假设 大麻的四种生物活性成分的组合协同作用，以防止 两种啮齿动物模型中疼痛的发展：化疗引起的神经病理性疼痛和与 牙髓暴露。此外，这些大麻成分对吗啡的镇痛作用也将 被评估。大麻含有100多种植物大麻素以及几种萜类化合物，它们是 也具有生物活性。如RFT-AT-19-008中所述，而越来越多的文献表明大麻 可能具有镇痛特性，植物大麻素∆9-四氢大麻酚的精神活性作用 (THC)限制其用途，呼吁调查更多植物大麻素的治疗潜力 以及在植物中发现的萜类化合物。我们实验室一直在研究非胰岛素样物质的抗神经病疗效。 精神活性植物大麻素大麻二醇(CBD)已有十多年的历史。除了CBD，未成年人 大麻素大麻酚(CbG)，四氢呋喃的酸性形式，和萜烯-β-石竹烯(β-CP)， 作为镇痛剂和/或抗炎药，越来越受到临床医生的关注。我们还有 最近证明β-CP可防止大鼠牙体机械敏感性的发展。 疼痛。重要的是，对大麻成分的所谓“随行效应”进行了详细的轶事讨论， 但令人遗憾的是，缺乏经验数据，包括THC以外协同作用的可能性。我们 确定CBD与THC协同作用以减轻与紫杉醇相关的机械性痛觉过敏 给药，同时减弱吗啡对热敏感性的抗伤害性作用。测试这类 交互效应要求对单一和联合制剂进行严格的剂量反应测试和分析， 这些要求随着要组合的代理数量的增加而增加。动物建模测试独一无二 几种大麻成分的相互作用为翻译提供了独特的有效贡献 医学，因为在临床环境中执行这样的研究要具有更大的挑战性和更高的成本。在 目前的建议我们将确定CBD、CBG、THCA和β-CP单独和联合使用的疗效 男性和女性的触觉超敏和其他与疼痛相关的行为。我们还将确定互动的 CBD、CBG、THCA、β-CP联合吗啡对急性抗伤害性疼痛和内脏痛的影响在 完成行为测试，补充细胞和分子方法也将被利用 描述单一药物和联合用药对疼痛和炎症标志物的影响。集结的队伍 拥有专业知识和协作关系，以确保建议的可行性和成果 项目。该项目的总体影响将是为以下主要组成部分提供经验性证据 大麻代表非精神活性的单一和/或组合，用于治疗急性和慢性疼痛。