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

使用质子磁共振波谱探索大麻二酚镇痛作用的机制。

• 批准号: 9893763
• 负责人: PERRY FRANKLIN RENSHAW
• 金额: $ 15.25万
• 依托单位: UNIVERSITY OF UTAH
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893763
• 关键词: Affect; Agonist; American; Analgesics; Animal Model; Anterior; Anti-inflammatory; Antiinflammatory Effect; Biological; Brain; Brain Chemistry; Brain region; Butyric Acids; CNR1 gene; CNR2 gene; Cannabidiol; Cannabinoids; Cannabis; Chemical Structure; Chemicals; Clinical Research; Cognitive; Collection; Complex; Creatine; Dependence; Development; Disease; Endocannabinoids; Equilibrium; Exhibits; G-Protein-Coupled Receptors; GABA-A Receptor; Glutamates; Glutamine; Goals; Human; Inferior; Inflammation; Inflammatory; Insula of Reil; Interleukin-6; Isomerism; Literature; Magnetic Resonance Spectroscopy; Measurement; Measures; Medical; Methods; N-acetylaspartate; Neurotransmitters; Opioid; Pain Threshold; Pain intensity; Pain management; Peripheral; Pharmaceutical Preparations; Pharmacologic Actions; Pharmacology; Placebos; Plants; Policies; Preparation; Process; Property; Protons; Publishing; Quality Control; Randomized Controlled Trials; Regulation; Reporting; Research; Risk; Serotonin; Serotonin Receptor 5-HT1A; Signal Transduction; Signaling Molecule; TNF gene; Techniques; Terpenes; Testing; Tetrahydrocannabinol; Therapeutic; Therapeutic Effect; Vanilloid; Visual; analog; animal pain; capsaicin receptor; chronic pain; chronic pain patient; cingulate cortex; clinically significant; cytokine; digital; evidence base; gamma-Aminobutyric Acid; in vivo; inflammatory marker; innovation; insight; marijuana use; marijuana user; myoinositol; neurobiological mechanism; neurochemistry; neuroimaging; neuroinflammation; novel strategies; opioid epidemic; pain model; pain processing; pain relief; positive allosteric modulator; pre-clinical research; preclinical study; receptor; relating to nervous system; side effect; two-dimensional

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.

项目摘要/摘要：慢性疼痛是一种影响大约一亿美国人的普遍疾病。 然而，慢性疼痛的治疗在很大程度上依赖于阿片类药物。阿片类药物的使用伴随着 重大缺陷包括缺乏长期疗效以及依赖的风险 对全国阿片类药物流行作出了重大贡献。因此，新颖的开发和鉴定 慢性疼痛的疼痛管理策略是一个未得到满足的关键需求。蓬勃发展的文学体系 表明大麻植物具有镇痛特性，据报道的治疗效果包括 在临床前和临床研究中具有实质性和结论性。其主要精神活性成分 然而，大麻植物四氢大麻酚 (THC) 已显示出镇痛作用；它的使用受到限制 不良的精神和认知影响。然而，并非所有 THC 异构体​​都具有精神活性 影响。例如，大麻二酚 (CBD) 已被证明具有镇痛特性，且无需 精神作用。 CBD 镇痛功效的生物学机制相对较 尚未探索，因此需要进行机制研究来调查这一研究问题。 CBD有一个 对多种受体具有激动剂和拮抗剂活性的复杂药理学，包括但不限于 内源性大麻素 CB1 和 CB2 受体、血清素 5-HT1A 受体、γ-氨基丁酸受体 (GABA-A) 和香草酸受体。此外，CBD 是一种有效的抗炎剂，已被证明可以减少 细胞因子和其他促炎信号分子的水平。拟议研究的目标 响应 RFA-AT-19-009，用于评估短期（5 天）给药后大脑化学变化 使用质子磁共振波谱 (1H-MRS) 分析富含 CBD 的大麻提取物。 1H-MRS 允许测量脑代谢物的体内水平，例如 N-乙酰天冬氨酸、肌酸、乳酸、 谷氨酸、GABA、谷氨酰胺 (Gln) 和肌醇 (mL)。慢性疼痛的 MRS 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 疼痛还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 能张力的药物可能表现出有效的镇痛作用 活动。通过拟议的研究，我们的目的是调查短期服用大麻是否有效 富含 CBD 的提取物可以调节关键疼痛处理区域的谷氨酸和 GABA 信号 大脑，例如前扣带皮层 (ACC) 和岛叶。此外，我们计划调查 CBD 对炎症的外周和神经标志物的影响。研究的顺利完成将 推进 CBD 作为疼痛疾病潜在治疗方法的循证应用，也将 提供可靶向减少神经炎症的底物。