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

项目摘要 神经病理性疼痛是由躯体感觉神经系统受损引起的，由此产生的疼痛有严重的 对生产力、情绪和整体生活质量的影响。大麻已经被使用了数千年 作为一种有效的止痛药。然而，其主要大麻素成分-9-四氢大麻酚(THC)， 有很强的精神副作用，限制了其用于疼痛治疗。第二丰度成分 在大麻中，大麻二醇(CBD)可以提供疼痛缓解而不产生重大的精神影响，但其止痛剂 效果不如THC或大麻那么强。有趣的是，临床和临床前研究都表明 THC和CBD按固定比例给药可产生更好的止痛效果，并避免不良反应 效果。然而，THC和CBD协同作用的潜在机制仍不清楚。这个 本研究补充的父项目旨在确定神经机制并提供优化 CBD介导的镇痛作用。本附录的总体目标是研究神经 THC和CBD协同作用以优化镇痛效力的机制 并将精神副作用降至最低。在目标1中，我们将确定THC：CBD是否与不同的神经联系 神经病理性疼痛小鼠模型中电路激活模式与单一药物的比较。在目标2中，我们将 确定THC：CBD是否在钙活动和内源性大麻素之间进行明显的动态耦合 (ECB)信号传递与单一药物相比。这些拟议的研究将有助于母项目的整体 明确大麻素的镇痛机制和提高其治疗潜力的前提 增加了一个创新和研究不足的研究部分。揭示特定的神经激活和ECB THC诱导的信号变化：CBD不仅将促进对大麻协同作用的机械性理解， 还可以进行治疗靶点的识别和优化。

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.