Analgesic efficacy of single and combined minor cannabinoids and terpenes

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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.