Exploring the mechanisms underlying the analgesic effect of Cannabidiol using Proton Magnetic Resonance Spectroscopy.

项目摘要/摘要：慢性疼痛是一种流行的疾病，影响着大约1亿美国人。 慢性疼痛的治疗严重依赖阿片类药物；阿片类药物的使用伴随着 重大缺陷，包括长期缺乏有效性和依赖的风险 对全国阿片类药物流行起到了重要作用。因此，小说的发展和认同 慢性疼痛的疼痛管理策略是一个关键的未得到满足的需求。蓬勃发展的文学体裁 表明大麻植物具有止痛特性，据报道，其治疗效果从 在临床前和临床研究中都有实质性的到决定性的研究。人体内主要的精神活性成分 大麻植物四氢大麻酚(THC)已显示出止痛作用，但其使用受到以下限制 不利的精神活动和认知影响。然而，并不是所有的THC异构体都显示出精神活性。 效果。例如，大麻二酚(CBD)已被证明具有止痛特性，而不是 精神活性效应。CBD止痛作用的生物学机制是相对 需要对这一研究问题进行未经探索的、因此是机械性的研究。CBD有一个 在几种受体上具有激动剂和拮抗剂活性的复杂药理作用，包括但不限于 内源性大麻素CB1和CB2受体、5-羟色胺5-HT1a受体、γ-氨基丁酸受体 (GABA-A)和香草素受体。此外，CBD是一种有效的抗炎药物，并已显示出减少 细胞因子和其他促炎信号分子的水平。拟议研究的目标是 对RFA-AT-19-009的响应是评估短期(5天)给药后脑化学的变化 使用质子磁共振波谱(1H-MRS)对富含CBD的大麻提取物进行分析。1H-MRS 允许测量体内大脑代谢物的水平，如N-乙酰天冬氨酸、肌酸、乳酸、 谷氨酸、GABA、谷氨酰胺(Gln)和肌醇(Mi)。MRS对慢性疼痛的研究表明 大脑关键疼痛处理区域谷氨酸和GABA信号的变化。此外，慢性 疼痛也与促炎信号分子水平升高有关。因此， 能够调节中枢谷氨酸和GABA能张力的药物可能具有有效的止痛作用 活动。通过这项拟议的研究，我们的目标是调查短期服用大麻是否 富含CBD的提取物可调节大鼠痛觉关键区域的谷氨酸和GABA能信号 大脑，如前扣带回皮质(ACC)和脑岛。此外，我们计划调查 CBD对外周和神经炎症标志物的影响这项研究的成功完成将会 推动CBD作为一种潜在的疼痛治疗方法的循证应用，并将 提供可靶向减少神经炎症的底物。

Project Summary/Abstract: Chronic pain is a prevalent disorder affecting approximately 100 million Americans. Treatment of chronic pain has heavily relied on opioid drugs, however; the use of opioids is accompanied with significant shortcomings including lack of efficacy in the long term and the risk for dependence that has contributed significantly to the national opioid epidemic. Thus, development and identification of novel strategies for pain management in chronic pain is a critical unmet need. A burgeoning body of literature suggests that the Cannabis plant has analgesic properties, with reported therapeutic effects ranging from substantial to conclusive in both preclinical and clinical studies. The main psychoactive constituent in the cannabis plant, tetrahydrocannabinol (THC) has demonstrated analgesic effects, however; its use is limited by adverse psychoactive and cognitive effects. However, not all isomers of THC demonstrate psychoactive effects. For example, cannabidiol (CBD) has been shown to demonstrate analgesic properties without psychoactive effects. The biological mechanisms underlying the analgesic efficacy of CBD are relatively unexplored and hence mechanistic studies investigating this research question are needed. CBD has a complex pharmacology with agonist and antagonist activity at several receptors including but not limited to endocannabinoid CB1 and CB2 receptors, serotonin 5-HT1A receptors, gamma-amino butyric acid receptors (GABA-A), and vanilloid receptors. In addition, CBD is a potent anti-inflammatory and has shown to decrease levels of cytokines and other pro-inflammatory signaling molecules. The goal of the proposed study, which responds to RFA-AT-19-009, is to evaluate changes in brain chemistry after a short-term (5-day) administration of a cannabis extract enriched in CBD using proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS allows the measurement of in vivo levels of brain metabolites such as N-acetylaspartate, creatine, lactate, glutamate, GABA, glutamine (Gln), and myoinositol (mI). MRS studies of chronic pain have demonstrated changes in glutamate and GABA signaling in critical pain-processing regions of the brain. Furthermore, chronic pain has also been associated with increased levels of pro-inflammatory signaling molecules. Thus, pharmacological agents that can modulate central glutamate and GABAergic tone may exhibit potent analgesic activity. With the proposed study, we aim to investigate whether a short-term administration of a cannabis extract enriched in CBD can modulate glutamate and GABAergic signaling in critical pain-processing regions of the brain such as the anterior cingulate cortex (ACC) and insula. Furthermore, we plan to investigate the effects of CBD on peripheral and neural markers of inflammation. The successful completion of the study will advance the evidence-based application of CBD as a potential treatment for pain conditions and will also provide substrates that can be targeted to reduce neuroinflammation.