Mechanism and Optimization of CBD-mediated analgesic effects

CBD介导的镇痛作用机制及优化

• 批准号: 10018669
• 负责人: ZHIGANG HE
• 金额: $ 67.09万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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/10018669
• 关键词: Absence of pain sensation; Adult; Analgesics; Attenuated; Binding; Brain Stem; Calcium; Cannabidiol; Cannabinoids; Cannabinol; Cannabis; Cerebral cortex; Chlorides; Data; Disinhibition; Dorsal; Dose; Family; GABA Receptor; Glycine; Glycine Receptors; Hyperactive behavior; Image; Imaging technology; Immediate-Early Genes; Impairment; In Vitro; Intrathecal Injections; Killer Cells; Knock-out; Light; Lumbar spinal cord structure; Maps; Mechanics; Mediating; Medical; Methods; Minor; Modeling; Molecular; Monitor; Mus; Neural Inhibition; Neurons; Pain; Pain management; Peripheral; Peripheral nerve injury; Pharmacology; Publications; Receptor Cell; Reporter Genes; Route; Signal Transduction; Somatosensory Cortex; Spinal; Spinal Cord; Stimulus; Structure; Testing; Tetrahydrocannabinol; Viral Vector; base; blood-brain barrier crossing; cannabichromene; cannabigerol; cell type; cellular targeting; chloride-cotransporter potassium; chronic pain; design; effective therapy; in vivo; inflammatory pain; inhibitor/antagonist; innovation; insight; marijuana use; nerve injury; neuromechanism; novel; novel strategies; pain model; painful neuropathy; response; side effect; small hairpin RNA; somatosensory; spared nerve; transmission process

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.

抽象的 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。次要的 大麻素，例如大麻二酚（CBD），不具有精神活性。但它们的镇痛作用 不如 THC 有效，并且少量大麻素介导的镇痛可能通过神经机制进行 优化仍然很大程度上未知。因此，该项目的总体目标是识别神经网络 涉及次要大麻素信号传导的机制，以优化其镇痛效果。鉴于 令人信服的证据表明 CBD 作用于 a1 和 a3-甘氨酸受体 (GlyR)，它们只是分子信号的一部分 对于神经性疼痛的参与者，我们将研究 CBD 或其他药物组合的作用和机制 基于 KCC2（一种在大多数细胞中表达的神经元特异性氯化物挤出机）进行操作的次要大麻素 神经元。我们的测试假设是 CBD 的机械效应可能受到 KCC2 剂量依赖性的调节 增加脊髓和/或皮质中的 KCC2 活性可能会增强 CBD 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性方式改变 CBD 镇痛，并定义 KCC2 调节 CBD 镇痛的电路机制。除了 CBD 之外，我们还将研究是否 KCC2 活性将调节 CBD 相关的次要大麻素家族的镇痛作用。识别 次要大麻素介导的镇痛的新电路目标和机制不仅有助于优化非 基于精神活性大麻素的疗法，但也提供了开发有效新疗法的途径 副作用最小。