Mechanism and Optimization of CBD-mediated analgesic effects

摘要 大量证据表明，大麻是有效的治疗慢性疼痛的成年人， 大麻的使用受到其主要精神活性成分四氢大麻酚的限制。轻微 大麻素，如大麻二酚（CBD），不具有精神活性。然而，它们的镇痛作用 不像THC那样有效，并且少量大麻素介导的镇痛可能是神经机制。 优化仍然在很大程度上未知。因此，本项目的总体目标是识别神经 研究人员还发现，大麻素参与次要大麻素信号传导的机制，以优化其镇痛作用。鉴于 令人信服的证据表明，CBD作用于α 1和α 3-甘氨酸受体（GlyR），这只是分子的一部分， 在神经性疼痛的球员，我们将调查的CBD或其他组合的效果和机制， 少量大麻素与基于KCC 2的操作，KCC 2是一种神经元特异性氯化物挤出机，在大多数人中表达， 神经元我们的检验假设是CBD的机制作用可能受到KCC 2剂量依赖性的调节 增加脊髓和/或皮质中KCC 2活性可增强CBD镇痛。具体来说，我们将 确定调节KCC 2活性是否会以剂量依赖性方式改变CBD镇痛，并定义 KCC 2调节CBD镇痛的电路机制。除了CBD，我们还将研究 KCC 2活性将调节CBD相关次要大麻素家族的镇痛作用。识别 新的回路靶点和微量大麻素介导的镇痛机制不仅有助于优化非- 精神活性大麻素为基础的疗法，而且还提供了开发有效的新治疗方法的途径， 最小的副作用

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.