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: 10013187
• 负责人: Adrianne Rae Wilson-Poe
• 金额: $ 24.9万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013187
• 关键词: Absence of pain sensation; 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; pain relief; protein distribution; protein protein interaction; side effect; 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.

项目总结 这项研究的目的是描述u-阿片和cb1-大麻素之间的相互作用。 疼痛时的感受器。阿片类药物的止痛特性是众所周知的，而且由于最近的 医用大麻合法化在美国许多州，大麻正越来越多地被用作 止痛药。越来越多的证据表明，大麻素和阿片系统在几个 这些方法可能具有显著的治疗效果。然而，大麻素/阿片类药物的作用机制 相互作用，以及大麻素/阿片类药物联合给药的滥用潜力尚未确定 已澄清。因此，我们建议表征阿片类药物和大麻素之间的相互作用。 这些药物可用于止痛作用的条件；具体地说，在 炎症性和神经性疼痛。这个为期五年的独立之路项目有三个具体的 目标。第一个目标(在指导的K99阶段)将描述CB1中疼痛诱导的适应 受体系统。第二个目标(在R00阶段)将决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性和神经性疼痛。而目标2中的研究将提供 重要的临床洞察力，安全实施新的止痛策略需要彻底 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发现，其中的实验提供了额外的好处 使用尖端的光遗传技术绘制相对模糊的导水管周围灰质。这个 在这些独立目标上的学习将我计划获得的技能与我广泛的 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 在下行痛觉通路中。拟议研究的完成将使我能够完成我的 近期目标是进一步确定大麻素/阿片类药物相互作用的特征。它还直接对我的 开发新疗法的长期目标，在最大限度地增加止痛的同时将不良反应降至最低 效果。这个独立之路项目也为我提供了过渡的关键机会 从有指导的实习生到终身教职的独立调查员。导师何塞·莫伦-康塞普西翁是 这个项目的理想监督者，因为他在动机行为和分子生物化学方面的经验是 对把我的工作带到未来至关重要。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Robert Gereau同样适合扩展我的技能，包括切割 边缘元素将显著提升我的工作的影响力。此外，世界一流的设施 华盛顿大学将提供一个完美的培训环境，在其中我可以完成我的目标 并成功过渡到独立。