Mechanism and optimization of CBD-mediated analgesic effects (Diversity Supplement)

CBD介导的镇痛作用的机制和优化（多样性补充）

• 批准号: 10714331
• 负责人: ZHIGANG HE
• 金额: $ 2.82万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10714331
• 关键词: Absence of pain sensation; Affective; Affinity; Analgesics; Animal Model; Animals; Binding; Brain; CNR1 gene; CNR2 gene; Calcium; Calcium Signaling; Cannabidiol; Cannabinoids; Cannabis; Cannabis sativa plant; Cells; Characteristics; Clinical Research; Clinical Trials; Coupling; Development; Endocannabinoids; Enzymes; Feedback; Future; Hyperactivity; In Vitro; Ion Channel; Label; Maps; Mediating; Medical; Minor; Modeling; Molecular Target; Moods; Mus; Nervous System; Neurons; Pain; Pain management; Parents; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Production; Productivity; Quality of life; Regulation; Reporting; Research; Role; Sativex; Somatosensory Cortex; Spinal; Synaptic Transmission; System; Techniques; Testing; Tetrahydrocannabinol; Therapeutic; Vertebral column; Work; allodynia; behavioral response; cell type; chronic pain management; dosage; endocannabinoid signaling; endogenous cannabinoid system; improved; in vivo; innovation; insight; mouse model; nerve injury; neural; neural circuit; neuromechanism; pain model; pain reduction; pain relief; painful neuropathy; parent project; preclinical study; prevent; receptor; response; sensor; side effect; somatosensory; spared nerve; synergism; therapeutic target; treatment strategy

Project Summary Neuropathic pain is caused by damage to the somatosensory nervous system and the resulting pain has serious consequences to productivity, mood, and overall quality of life. Cannabis sativa has been used for thousands of years as a potent analgesic. However, its main cannabinoid component, delta-9-tetrahydrocannabinol (THC), has strong psychotropic side effects which restrict its usage for pain treatment. The second abundant constituent of cannabis, cannabidiol (CBD), can provide pain relief without major psychotropic effects, but its analgesic effects are not as potent as THC or cannabis. Interestingly, both clinical and preclinical studies suggest that administration of THC and CBD in a fixed ratio results in superior analgesic effects and avoids unwanted side effects. However, the mechanisms underlying the synergistic actions of THC and CBD remain unknown. The parent project to this research supplement aims to identify the neural mechanisms and provide optimization of CBD-mediated analgesic effects. The overall objective for this supplement is to investigate the neural mechanisms underlying the synergistic actions of THC and CBD in order to optimize analgesic potency and minimize psychotropic side effects. In Aim 1, we will determine if THC:CBD engages distinct neural circuit activation patterns compared to single drugs in a neuropathic pain mouse model. In Aim 2, we will determine if THC:CBD engages distinct dynamic coupling between calcium activities and endocannabinoid (eCB) signaling compared to single drugs. These proposed studies will contribute to the parent project’s overall premise of identifying the analgesic mechanisms and improving the therapeutical potentials of cannabinoids by adding an innovative and understudied research component. Revealing specific neural activation and eCB signaling changes induced by THC:CBD will advance not only mechanistic understanding of cannabis synergy, but also therapeutic target identification and optimization.

项目摘要 神经性疼痛是由对体感神经系统的损害引起的，由此产生的疼痛严重 生产力，情绪和整体生活质量的后果。大麻sativa已用于数千个 多年作为潜在的镇痛药。但是，其主要大麻素成分，delta-9-四氢大麻酚（THC）， 具有强大的精神副作用，限制了其用于疼痛治疗的用法。第二富人构成 大麻，大麻二酚（CBD）可以提供疼痛缓解而没有重大的精神作用，但其镇痛作用 影响不如THC或大麻的潜力。有趣的是，临床和临床前研究都表明 以固定比率给予THC和CBD会产生出色的镇痛作用，并避免不必要的侧面 效果。但是，THC和CBD的协同作用的基础机制仍然未知。这 该研究补充剂的父母项目旨在识别神经机制并提供优化 CBD介导的镇痛作用。该补充剂的总体目的是研究神经 THC和CBD协同作用的基础机制，以优化镇痛效力 并最大程度地减少精神副作用。在AIM 1中，我们将确定THC：CBD是否参与不同的神经 与神经性疼痛小鼠模型中的单一药物相比，电路激活模式。在AIM 2中，我们将 确定thc：cbd是否在钙活动和内源性大麻素之间参与不同的动态耦合 （欧洲央行）与单一药物相比发出信号。这些拟议的研究将有助于父母项目的整体 识别镇痛机制并改善大麻素的治疗潜力的前提 添加创新的研究组成部分。揭示特定的神经激活和欧洲央行 THC引起的信号传导变化：CBD不仅会提高对大麻协同作用的机理理解，还会提高 而且还需要热目标识别和优化。