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: 9895145
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895145
• 关键词: Absence of pain sensation; Acetic Acids; Achievement; Acids; Acute; Acute Pain; Agonist; Analgesics; Animal Model; Anti-Inflammatory Agents; Attenuated; Behavior; 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; conditioning; 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实证和定量检验假设， 大麻的四种生物活性成分的组合协同作用， 在两种啮齿动物模型中疼痛的发展：化疗诱导的神经性疼痛和 牙髓暴露。此外，这些大麻成分对吗啡镇痛的影响，也将 被评估。大麻含有超过100种植物大麻素以及几种萜烯化合物， 也具有生物活性。如RFT-AT-19-008所述，虽然越来越多的文献表明大麻 可能具有镇痛作用，植物大麻素β 9-四氢大麻酚的精神作用 (THC)限制其效用，要求对其他植物大麻素的治疗潜力进行调查 以及植物中发现的萜烯我们的实验室一直在研究抗神经病疗效的非- 精神活性植物大麻素大麻二酚（CBD）超过十年。除了CBD， 大麻素大麻萜酚（CBG），THC THCA的酸形式，和萜烯β-carbellene（β-CP），是 作为镇痛剂和/或抗炎剂受到临床医生越来越多的关注。我们还 最近证明，β-CP可以防止大鼠牙本质模型中机械敏感性的发展， 痛苦重要的是，大麻成分的所谓“随从效应”被详细讨论， 但令人遗憾的是，缺乏经验数据，包括THC之外协同相互作用的潜力。我们 确定CBD与THC协同作用以减轻与紫杉醇相关的机械性异常性疼痛 施用，同时减弱吗啡对热敏感性的抗伤害感受作用。测试这些 相互作用需要对单一和组合药剂进行严格的剂量反应测试和分析， 并且这些要求随着要组合的试剂的数量而增加。动物模型来测试独特的 几种大麻成分的相互作用提供了一种独特的有效的贡献， 在医学中，因为在临床环境中执行这样的研究是非常具有挑战性和昂贵的。在 目前的建议，我们将确定CBD，CBG，THCA和β-CP单独和组合的疗效， 男性和女性的触觉异常性疼痛和其他疼痛相关行为。我们还将确定互动 CBD、CBG、THCA和β-CP与吗啡对急性抗伤害性疼痛和内脏痛的影响。在 完成行为测试后，将利用补充的细胞和分子方法， 表征单一和组合药剂对疼痛和炎症标志物的作用。集合的团队 拥有专业知识和合作关系，以确保可行性和实现拟议的 项目该项目的总体影响将是为以下关键组成部分提供实验性证据： 大麻代表用于治疗急性和慢性疼痛的非精神活性单一和/或组合。