Role of CB1 Receptors in Opioid Tolerance During Pain

项目摘要 本研究的目的是表征μ-阿片和CB 1-大麻素之间的相互作用 感受器在疼痛中阿片类药物的镇痛特性是众所周知的，并且由于最近的 随着美国许多州的药用大麻合法化，大麻越来越多地被用作 止痛药越来越多的证据表明，大麻素和阿片系统在几个方面相互作用。 这些方法可能具有重要的治疗效用。然而，大麻素/阿片类药物的机制 相互作用，以及大麻素/阿片类药物联合给药的滥用可能性尚未得到证实。 阐明。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使用的条件;具体而言， 炎性和神经性疼痛。这个为期五年的独立之路项目有三个具体目标， 目标。第一个目标（在指导K99阶段）将描述CB 1中疼痛诱导的适应性 受体系统第二个目标（在R 00阶段）将确定联合治疗的疗效和安全性。 大麻素/阿片类药物治疗炎性和神经性疼痛。虽然目标2中的研究将提供 重要的临床见解，安全实施新的镇痛策略需要一个彻底的 了解大麻素/阿片类药物相互作用的神经机制。这些机制 将在本提案的第三个目标中揭示，其中的实验提供了一个额外的好处， 利用尖端的光遗传学技术绘制相对模糊的导水管周围灰质。的 在这些独立的目标研究无缝融合的技能，我建议获得与我的广泛 在慢性吗啡诱导适应的行为药理学和体外生理学方面的专业知识 在下行疼痛通路中。完成拟议的研究将使我能够完成我的 进一步表征大麻素/阿片类药物相互作用的直接目标。它也直接有助于我的 长期目标是开发新的治疗方法，最大限度地提高镇痛效果，同时最大限度地减少负面影响 方面的影响.这个独立之路项目也为我提供了一个关键的机会， 从实习生到终身独立调查员导师何塞·莫隆-康塞普西翁是 理想的主管这个项目，因为他的经验与动机行为和分子生物化学是 这对我的工作走向未来至关重要。作为慢性疼痛领域的世界领导者和 体外光遗传学，共同导师罗伯特Gereau同样很适合扩展我的技能，包括切割 能显著提升我作品影响力的边缘元素此外，世界一流的设施， 华盛顿大学将提供一个无可挑剔的培训环境，在那里我可以完成我的目标 成功过渡到独立。

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.