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的损伤引起的，并且所产生的疼痛具有严重的神经病理性疼痛。 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 多年来作为一种强效止痛剂。然而，它的主要大麻素成分，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。第二丰富组分 大麻，大麻二酚（CBD），可以提供疼痛缓解没有主要的精神影响，但其镇痛 效果不如四氢大麻酚或大麻。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导致上级镇痛效果并避免不需要的副作用 方面的影响.然而，THC和CBD协同作用的机制仍然未知。的 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。本补充的总体目标是调查神经 THC和CBD协同作用的潜在机制，以优化镇痛效力 尽量减少精神上的副作用在目标1中，我们将确定THC：CBD是否与不同的神经系统 神经病理性疼痛小鼠模型中与单一药物相比的回路激活模式。在目标2中，我们将 确定THC：CBD是否在钙活性和内源性大麻素之间进行了独特的动态耦合 (eCB)与单一药物相比。这些拟议的研究将有助于母项目的整体 确定镇痛机制和提高大麻素治疗潜力的前提， 增加了一个创新的和未充分研究的研究组成部分。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理解， 还包括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.