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.

项目概要 神经性疼痛是由体感神经系统受损引起的，由此产生的疼痛具有严重的 对生产力、情绪和整体生活质量的影响。大麻已被用于数千 多年来作为一种有效的镇痛剂。然而，其主要大麻素成分δ-9-四氢大麻酚（THC）， 具有强烈的精神副作用，限制了其用于疼痛治疗的用途。第二丰富的成分 大麻中的大麻二酚 (CBD) 可以缓解疼痛，但不会产生重大精神作用，但其镇痛作用 效果不如四氢大麻酚或大麻那么有效。有趣的是，临床和临床前研究都表明 以固定比例施用 THC 和 CBD 可产生优异的镇痛效果并避免不必要的副作用 影响。然而，THC 和 CBD 协同作用的机制仍然未知。这 本研究补充的母项目旨在确定神经机制并提供优化 CBD 介导的镇痛作用。本补充的总体目标是研究神经 THC 和 CBD 协同作用的机制，以优化镇痛效力 并尽量减少精神药物的副作用。在目标 1 中，我们将确定 THC:CBD 是否参与不同的神经网络 神经病理性疼痛小鼠模型中与单一药物相比的电路激活模式。在目标 2 中，我们将 确定 THC:CBD 是否参与钙活性和内源性大麻素之间的明显动态耦合 (eCB) 信号传导与单一药物相比。这些拟议的研究将有助于母项目的整体 确定镇痛机制并提高大麻素治疗潜力的前提是 增加一个创新的、未被充分研究的研究部分。揭示特定的神经激活和 eCB THC:CBD 引起的信号变化不仅将促进对大麻协同作用的机制理解， 还包括治疗靶点的识别和优化。