Mechanism and Optimization of CBD-mediated analgesic effects

摘要 大量证据表明，大麻对治疗成人慢性疼痛有效，但医学上 大麻的使用受到其主要精神活性成分四氢大麻酚(THC)的限制。小调 大麻二酚(CBD)等大麻素类物质不具有精神活性。然而，它们的止痛作用 没有THC和神经机制那么有效，小麻素介导的止痛可能通过这些机制 优化后的产品在很大程度上仍不为人所知。因此，这个项目的总体目标是识别神经细胞 参与小麻素信号传导的机制，以优化其止痛效果。根据…… CBD作用于A1和A3-甘氨酸受体(GlyRs)的令人信服的证据，这两种受体只是分子的一部分 在神经病理性疼痛的玩家中，我们将探讨CBD或其他药物联合使用的效果和机制 基于KCC2的少量大麻类化合物的操作，KCC2是一种在大多数情况下表达的神经元特异性氯挤出器 神经元。我们的检验假设是CBD的机械效应可能被KCC2剂量依赖地调制 增加脊髓和/或皮质的KCC2活性可能增强CBD的镇痛作用。具体来说，我们将 确定调节KCC2活性是否会以剂量依赖的方式改变CBD的止痛，并确定 KCC2调节CBD镇痛的电路机制。除了CBD，我们还将研究是否 KCC2活性将调节一系列与CBD相关的小麻素的止痛效果。识别 新的电路靶点和机制的小大麻介导的镇痛将不仅有助于优化非 精神活性大麻素疗法，也提供了开发有效的新疗法的途径 副作用最小。

Abstract Substantial evidence indicates that cannabis is effective for the treatment of chronic pain in adults, but medical use of cannabis is restricted by its main psychoactive component tetrahydrocannabinol (THC). Minor cannabinoids, such as cannabidiol (CBD), do not have psychotropic activity. However, their analgesic effects are not as potent as THC and the neural mechanisms by which minor cannabinoids-mediated analgesia may be optimized remain largely unknown. Accordingly, the overall objective of this project is to identify neural mechanisms involved in minor cannabinoids signaling in order to optimize their analgesic effects. In light of compelling evidence that CBD acts on a1 and a3-glycine receptors (GlyRs), which are only a part of molecular players in neuropathic pain, we will investigate the effects and mechanisms of the combination of CBD or other minor cannabinoids with manipulations based on KCC2, a neuron-specific chloride extruder expressed in most neurons. Our test hypothesis is that CBD's mechanistic effects may be modulated by KCC2 dose-dependently and increasing KCC2 activity in spinal cord and/or cortex may enhance CBD analgesia. Specifically, we will determine whether modulating KCC2 activity will alter CBD analgesia in a dose-dependent manner, and define circuit mechanisms by which KCC2 modulates CBD analgesia. In addition to CBD, we will also examine whether KCC2 activity will regulate the analgesic effects of a family of CBD-related minor cannabinoids. Identifying the novel circuit targets and mechanisms of minor cannabinoids-mediated analgesia will not only help optimize non- psychoactive cannabinoid-based therapies but also provide routes to develop effective new treatments with minimal side-effects.