Analgesic efficacy of single and combined minor cannabinoids and terpenes

受资助的R 01的主要目标是定量测试四种生物学特性的组合 大麻的活性成分协同作用，以防止神经病变的发展， 痛苦本增刊中提出的实验将检验这些非精神活性物质 这些化合物将通过抗炎和抗炎作用改善与年龄和阿尔茨海默病相关的认知障碍， 神经可塑性机制大麻的主要精神活性成分是四氢大麻酚， (THC)与认知不良反应有关，非精神活性植物大麻素大麻素（CBD） 已经在临床前表现出学习和记忆的改善。生物多样性公约的潜在作用机制 一系列的治疗适应症目前正在调查中，其深刻的抗炎和 最令人感兴趣的神经保护特性。除了CBD，次要的大麻素大麻酚 (CBG)THC、THCA的酸形式和萜烯β-香芹烯（β-CP）， 作为潜在抗炎剂而感兴趣。例如，我们最近证明β-CP 在啮齿动物模型中预防神经性疼痛的发展， 小鼠脑缺血模型，两种作用均与小胶质细胞活化减少相关。这些 综合这些数据，迫使进一步的研究，以确定非精神活性大麻的影响， 用于治疗与年龄和阿尔茨海默氏症相关的认知障碍/痴呆的方法。这是特别 考虑到老年患者构成了大量且不断增长的医用大麻使用者群体，这一点非常紧迫。最后， 资助和拟议研究的一个关键重点是确定这些大麻的相互作用 选民。大麻成分的所谓“随从效应”被详细讨论，但 经验数据严重缺乏。测试这种交互作用需要严格的剂量反应测试 以及对单个和组合代理的分析。动物模型来测试几个独特的互动效果 大麻成分为转化医学提供了独特有效的贡献， 在临床环境中的研究是非常具有挑战性和昂贵的。在目前的补充中，我们 建议确定CBD，CBG，THCA和β-CP单独和联合使用对执行的有效性 功能和识别记忆，以及3xTg-AD小鼠。完成时 行为测试，补充免疫组织化学和分子方法将用于检查 通过表征单一和联合药物对神经系统炎症的作用， 胶质细胞活化和神经元和小胶质细胞BDNF表达。组建的团队拥有专业知识， 合作关系，以确保拟议项目的实现。该项目的总体影响 将为代表非精神活性的大麻的关键成分提供经验证据 单独和/或组合用于治疗认知衰退。

The primary goal of the funded R01 is to quantitatively test the hypothesis that combinations of four biologically active components of Cannabis sativa act synergistically to protect against the development of neuropathic pain. Experiments proposed in this supplement will test the hypothesis that these non-psychoactive compounds will ameliorate age- and Alzheimer’s related cognitive impairment through anti-inflammatory and neuroplastic mechanisms. While the primary psychoactive constituent of Cannabis ∆9-tetrahydrocannabinol (THC) is associated with cognitive adverse effects, the non-psychoactive phytocannabinoid cannabinoid (CBD) has shown improvements in learning and memory preclinically. Potential mechanisms of action of CBD for a range of therapeutic indications are currently under investigation, with its profound anti-inflammatory and neuroprotective properties of paramount interest. 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 as potential anti-inflammatory agents. For example, we have recently demonstrated that β-CP prevents the development of neuropathic pain in rodent models and significantly decreases secondary injury in a mouse model of cerebral ischemia, with both effects correlating to decreased microglial activation. These data taken together compel further research to determine the effects of non-psychoactive Cannabis-based approaches for the treatment of age- and Alzheimer’s-related cognitive impairment/dementia. This is especially pressing given that older patients make up a large and growing population of Medical Cannabis users. Lastly, a key focus of the funded and proposed research is to determine interactive effects of these Cannabis constituents. So-called “entourage effects” of Cannabis constituents are anecdotally discussed at length, but empirical data are woefully lacking. Testing for such interactive effects requires rigorous dose response testing and analysis across single and combined agents. 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 supplement we propose to determine the efficacy of CBD, CBG, THCA, and β-CP alone and in combination on executive function and recognition memory in young and old mice, as well as 3xTg-AD mice. At the completion of behavioral testing, complementary immunohistochemical and molecular approaches will be utilized to examine the underlying neuroinflammatory mechanisms by characterizing the effects of single and combined agents on glial activation and neuronal and microglial BDNF expression. The assembled team has the expertise and collaborative relationship to ensure the 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 cognitive decline.