Pharmacological interactions between conventional and biased MOR agonists

项目总结 我们的实验室致力于了解不同的配体如何调节u阿片受体的活性。 (MOR)以及差异激活如何保存或阻止通常由 这种受体上的药物。为此，博恩实验室致力于开发各种不同的“有偏见的”激动剂。 吗啡和脑啡肽由于其优先通过G蛋白途径而不是招募来传递信号的能力 β受体阻滞素2。我们的初步研究表明，我们最偏重G的化合物SR-17018确实 不会导致小鼠呼吸抑制，尽管它与热板中的吗啡具有相同的效力 伤害性试验。此外，与刺激老鼠奔跑行为的吗啡不同，SR-17018不会 引起多动症。当我们用SR-17018和吗啡治疗小鼠时，我们发现SR-17018阻止了吗啡- 诱发的多动症。我将继续使用βarrestin的MOR激动剂来表征行为反应 2-和G蛋白偏向配基，在运动活性和呼吸活性测定中以剂量-反应方式 抑制，以充分理解这种明显的竞争性相互作用的性质。 这项建议旨在获得行为和体外药理学方面的培训，以确定MOR的阿片类药物相互作用 在老鼠身上。我将接受行为研究的执行和设计方面的培训，获取药代动力学数据， 以及对脑区受体信号的评估。此外，我的培训将需要获得对 GPCR药理学原理基础。我最初将使用药物强化的小鼠模型；我的 通过参加神经生物学的正式课程，将加强对成瘾行为的理解培训 通过参加提案中概述的有重点的成瘾研究会议。这些研究 这一应用的结果将被用来确定辅助治疗可能的益处，以增强 抗伤害作用，同时降低不良反应的风险。这些研究将阐明这一角色和 小鼠偏向激动症的机制朝着更安全的疼痛治疗和药物的发展 并将为我提供所需的培训，以继续我的职业道路，成为一名独立的教员 成瘾科学的研究人员。

PROJECT SUMMARY Our laboratory focuses on understanding how different ligands can modulate the activity of the mu opioid receptor (MOR) and how differential activation may preserve or prevent physiological responses typically induced by drugs at this receptor. To this end, the Bohn lab has worked to develop diverse “biased” agonists that diverge from morphine and enkephalins by their ability to preferentially signal through G protein pathways over recruiting βarrestin2 to the receptor. Our preliminary studies suggest that SR-17018, our most G biased compound, does not induce respiratory suppression in mice, although it has the same potency as morphine in the hot plate nociception assay. Further, unlike morphine, which stimulates mouse running behavior, SR-17018 does not induce hyperactivity. When we treat mice with SR-17018 and morphine, we find that SR-17018 blocks morphine- induced hyperactivity. I will continue characterizing the behavioral responses using MOR agonists from βarrestin 2- and G protein-biased ligands, in a dose-response manner in the locomotor activity assay and respiratory suppression to fully understand the nature of this apparent competitive interaction. This proposal aims to attain training in behavioral and in vitro pharmacology to define opioid interactions at MOR in mice. I will gain training in execution and design of behavioral studies, acquisition of pharmacokinetic data, and evaluation of receptor signaling in brain regions. Further, my training will entail gaining understanding in fundamentals of GPCR pharmacological principles. I will use mouse models of drug reinforcement initially; my training in understanding addictive behaviors will be augmented by taking a formal course on the neurobiology of addiction and by participating in focused addiction research conferences outlined in the proposal. The studies resulting from this application will be used to identify possible benefits for adjuvant therapy to potentiate antinociception while decreasing the risk of adverse effects. These studies will shed light on the role and mechanism of biased agonism in mice towards the development of safer pain treatment and pharmaceuticals and will provide me the training that I need to continue my career path towards becoming an independent faculty researcher in addiction sciences.