Role of CB1 Receptors in Opioid Tolerance During Pain

CB1 受体在疼痛期间阿片类药物耐受性中的作用

• 批准号: 9243796
• 负责人: Adrianne Rae Wilson-Poe
• 金额: $ 13.8万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243796
• 关键词: Absence of pain sensation; Adverse effects; Amygdaloid structure; Analgesics; Anterior; Award; Behavior; Behavior Therapy; Biochemical; Biochemistry; Botanicals; CNR1 gene; Cannabinoids; Cannabis; Cellular Morphology; Chronic; Clinical; Clinical Research; Data; Development; Dose; Drug Interactions; Electrophysiology (science); Elements; Environment; Evolution; Future; Geographic state; Goals; In Vitro; Legal; Mediating; Medical Marijuana; Mentors; Molecular; Morphine; Opioid; Opioid Analgesics; Pain; Pathway interactions; Pharmaceutical Preparations; Phase; Physiological Adaptation; Physiology; Property; Rattus; Research; Research Personnel; Rewards; Role; Safety; Synapses; System; Technical Expertise; Techniques; Testing; Therapeutic; Training; Universities; Up-Regulation; Washington; Work; attenuation; behavioral pharmacology; chronic pain; cingulate cortex; coping; drug of abuse; experience; experimental study; gamma-Aminobutyric Acid; improved; inflammatory neuropathic pain; inflammatory pain; innovation; insight; midbrain central gray substance; motivated behavior; mu opioid receptors; neuromechanism; novel; novel therapeutics; opiate tolerance; opioid abuse; optogenetics; protein distribution; protein protein interaction; skills; tenure track; tool; transmission process

PROJECT SUMMARY The goal of this research is to characterize the interaction between the mu-opioid and CB1-cannabinoid receptors during pain. The analgesic properties of opioids are well known, and because of the recent legalization of medicinal cannabis in many US states, cannabis is increasingly being utilized as an analgesic. A growing body of evidence suggests that the cannabinoid and opioid systems interact in several ways that could be of significant therapeutic utility. However, the mechanisms of cannabinoid/opioid interactions, and the abuse potential of combined cannabinoid/opioid administration have yet to be elucidated. Therefore, we propose to characterize the interaction between opioids and cannabinoids in conditions during which these drugs might be used for their analgesic properties; specifically, in inflammatory and neuropathic pain. This five-year, Pathway to Independence project has three Specific Aims. The first Aim (during the mentored K99 phase) will characterize pain-induced adaptations in the CB1 receptor system. The second Aim (during the R00 phase) will determine the efficacy and safety of combined cannabinoid/opioid treatment of inflammatory and neuropathic pain. While the studies in Aim 2 will provide important clinical insight, safe implementation of novel analgesic strategies requires a thorough understanding of the neural mechanisms underlying cannabinoid/opioid interactions. These mechanisms will be uncovered in the third Aim of this proposal, and the experiments therein provide an added benefit of mapping the relatively nebulous periaqueductal gray, using cutting edge optogenetic techniques. The studies in these independent Aims seamlessly blend the skills I propose to acquire with my extensive expertise in the behavioral pharmacology and in vitro physiology of chronic morphine-induced adaptations in the descending pain pathway. The completion of the proposed studies will allow me to accomplish my immediate goal of further characterizing cannabinoid/opioid interactions. It also directly contributes to my long-term goal of developing novel therapies that maximize analgesia while minimizing negative side effects. This Pathway to Independence project also provides me with the critical opportunity to transition from mentored trainee to tenure-track independent investigator. The mentor Jose Moron-Concepcion is the ideal supervisor for this project, as his experience with motivated behavior and molecular biochemistry is critical in carrying my work into the future. As a world leader in the chronic pain field and an innovator in in vitro optogenetics, the co-mentor Robert Gereau is equally well suited to expand my skills to include cutting edge elements that will significantly elevate the impact of my work. Furthermore, the world-class facilities at Washington University will provide an impeccable training environment in which I can complete my goals and successfully transition to independence.

项目概要 本研究的目的是表征 mu-阿片类药物和 CB1-大麻素之间的相互作用 疼痛时的感受器。阿片类药物的镇痛特性是众所周知的，并且由于最近的研究 美国许多州药用大麻合法化，大麻越来越多地被用作 镇痛。越来越多的证据表明大麻素和阿片类药物系统在几个方面相互作用 可能具有重要治疗用途的方法。然而，大麻素/阿片类药物的作用机制 大麻素/阿片类药物联合给药的相互作用以及滥用可能性尚未确定 阐明了。因此，我们建议描述阿片类药物和大麻素之间的相互作用 这些药物可能因其镇痛特性而被使用的情况；具体来说，在 炎症性疼痛和神经性疼痛。这个为期五年的独立之路项目有三个具体内容 目标。第一个目标（在指导的 K99 阶段）将描述 CB1 中疼痛引起的适应 受体系统。第二个目标（在 R00 阶段）将确定联合用药的有效性和安全性 大麻素/阿片类药物治疗炎症和神经性疼痛。虽然目标 2 中的研究将提供 重要的临床见解，安全实施新型镇痛策略需要彻底的 了解大麻素/阿片类药物相互作用的神经机制。这些机制 将在该提案的第三个目标中揭示，其中的实验提供了额外的好处 使用尖端光遗传学技术绘制相对模糊的导水管周围灰质图。这 这些独立目标的研究将我打算获得的技能与我广泛的知识无缝地融合在一起 慢性吗啡诱导适应的行为药理学和体外生理学专业知识 在下行疼痛通路中。完成拟议的研究将使我能够完成我的任务 进一步表征大麻素/阿片类药物相互作用的近期目标。也直接对我的 开发新疗法的长期目标是最大限度地发挥镇痛作用，同时最大限度地减少负面影响 影响。这个独立之路项目也为我提供了重要的过渡机会 从受指导的实习生到终身教授独立调查员。导师何塞·莫龙-康塞普西翁 (Jose Moron-Concepcion) 是 该项目的理想主管，因为他在动机行为和分子生物化学方面的经验非常丰富 对于我今后的工作至关重要。作为慢性疼痛领域的世界领导者和创新者 体外光遗传学，联合导师 Robert Gereau 同样适合扩展我的技能，包括切割 边缘元素将显着提升我的工作的影响力。此外，世界一流的设施 华盛顿大学将提供无可挑剔的训练环境，让我能够完成我的目标 并成功过渡到独立。