Investigation of in vivo efficacy of G-protein biased mu opioid receptor agonists.

项目摘要 典型的μ-阿片受体（莫尔）激动剂（例如，羟考酮，芬太尼）是有效的镇痛剂， 治疗中度至重度疼痛。然而，典型的莫尔激动剂对疼痛的治疗窗口 管理受到其不想要的副作用如呼吸抑制和滥用倾向的限制。的 典型的莫尔激动剂的局限性促进了新型莫尔激动剂的开发（例如，PZM-21，SR- 17018）具有更有利的安全性。然而，这些新型激动剂产生的机制 它们更理想的行为效果仍然是未知的。有证据表明这些化合物 由于G蛋白信号传导偏向而表现出改善的副作用特征。然而，最近的工作 挑战了这一立场，有证据表明这些新的激动剂仅仅是部分激动剂， 莫尔。因此，对机制的体外研究的结果是相互矛盾的，体内研究也是相互矛盾的。 缺乏本研究的目的是研究一系列G蛋白偏向性莫尔激动剂的临床前应用。 模型的治疗和副作用，并在实验条件下，旨在区分典型的 部分莫尔激动剂。在这些条件下，典型的莫尔激动剂产生最大程度的作用， 而部分莫尔激动剂产生次最大程度的作用。具体而言，目标1将衡量 新型莫尔激动剂与典型和部分莫尔激动剂相比产生的镇痛强度 在不同水平的热伤害性刺激下，目标2将测量 与典型和部分莫尔激动剂相比，新型莫尔激动剂产生的呼吸抑制 在全身体积描记分析中。目标3将比较最大断点（滥用指标 易患性）在增加的条件下在自我给药测定中由典型的、部分的和新型的莫尔激动剂介导的 水平的操作性挑战提供了一个渐进的比例时间表的强化。根据 通过观察新型莫尔激动剂产生的行为效应，我们将能够确定 在体内最接近地重现。最终，我们对这三个目标的研究结果将为发展提供信息。 基于阿片类药物的治疗具有更有利的安全性和更宽的治疗窗口。完成 为了实现这些目标，本建议书中描述了培训计划，培训计划将在杰克逊校区进行 密西西比大学医学中心的一名医生。申请人将接受科学培训， 来自赞助商、赞助商的合作者、神经科学项目的专业发展，以及 健康科学研究生院

PROJECT SUMMARY Typical mu-opioid receptor (MOR) agonists (e.g., oxycodone, fentanyl) are efficacious analgesics for the treatment of moderate to severe pain. However, the therapeutic window of typical MOR agonists for pain management is limited by their unwanted side effects such as respiratory depression and abuse liability. The limitations of typical MOR agonists have prompted the development of novel MOR agonists (e.g., PZM-21, SR- 17018) with more favorable safety profiles. However, the mechanism by which these novel agonists produce their more desirable behavioral effects is still unknown. One body of evidence indicates that the compounds exhibit improved side-effect profiles due to G-protein signaling bias. However, more recent work has challenged this position with evidence indicating that these novel agonists are merely partial agonists at the MOR. Thus, the results from in vitro investigations into mechanisms are conflicting and in vivo studies are lacking. The purpose of this proposal is to investigate a series of G-protein biased MOR agonists in preclinical models of therapeutic and side effects, and under experimental conditions designed to differentiate typical from partial MOR agonists. Under these conditions, typical MOR agonists produce maximal magnitude of effects, and partial MOR agonists produce sub-maximal magnitude of effects. Specifically, Aim 1 will measure the magnitude of analgesia produced by novel MOR agonists in comparison to typical and partial MOR agonists under different levels of thermal nociceptive stimulation in a hot-plate assay. Aim 2 will measure the magnitude of respiratory depression produced by novel MOR agonists, in comparison to typical and partial MOR agonists in a whole-body plethysmography assay. Aim 3 will compare the maximum breakpoint (indicator of abuse liability) mediated by typical, partial, and novel MOR agonists in a self-administration assay under increasing levels of operant challenge provided by a progressive-ratio schedule of reinforcement. Based on the profile of behavioral effects engendered by the novel MOR agonists, we will be able to determine which in vitro position is most closely recapitulated in vivo. Ultimately, our findings from these three aims will inform the development of opioid-based therapeutics with more favorable safety profiles and wider therapeutic windows. To accomplish these aims, the training plan was described in this proposal, and, it will be carried out at the Jackson campus of the University of Mississippi Medical Center. The applicant will be receiving scientific training and professional development from the sponsor, the sponsor's collaborators, the Program In Neuroscience, and the School of Graduate Studies in the Health Sciences.