Pharmacological interactions between conventional and biased MOR agonists

传统 MOR 激动剂和偏向 MOR 激动剂之间的药理学相互作用

• 批准号: 10198773
• 负责人: AGNES M ACEVEDO-CANABAL
• 金额: $ 5.54万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198773
• 关键词: Acute; Addictive Behavior; Adjuvant Therapy; Adverse effects; Affect; Agonist; Analgesics; Behavior; Behavioral; Binding; Biological Assay; Brain Stem; Brain region; Career Choice; Cessation of life; Collection; Corpus striatum structure; Data; Development; Dose; Drug Evaluation; Drug Interactions; Drug Kinetics; Enkephalins; Evaluation; Extinction (Psychology); Faculty; Family; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Hyperactivity; In Vitro; Knock-out; Knockout Mice; Laboratories; Learning; Life; Ligands; Light; Measures; Mediating; Membrane; Morphine; Motor Activity; Mus; Narcotics; Nature; Neurobiology; Nociception; Opioid; Opioid Analgesics; Opioid agonist; Overdose; Pain; Pain management; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physiological; Property; Receptor Signaling; Regulation; Research; Research Personnel; Respiratory distress; Risk; Role; Running; Scaffolding Protein; Science; Sedation procedure; Series; Signal Transduction; Signaling Protein; Site; Testing; Training; Wild Type Mouse; Work; addiction; analog; behavioral response; behavioral study; brain tissue; conditioned place preference; design; drug reinforcement; improved; in vivo; insight; interest; member; mouse model; mu opioid receptors; neurochemistry; opioid epidemic; opioid use; overdose death; preservation; prevent; psychostimulant; receptor; recruit; respiratory; response; side effect; symposium; therapeutic opioid

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.

项目摘要 我们的实验室致力于了解不同的配体如何调节μ阿片受体的活性 (MOR)以及差异激活如何保持或防止通常由 药物在这个受体。为此，Bohn实验室致力于开发多样化的“偏向”激动剂， 吗啡和脑啡肽的能力，优先通过G蛋白途径的信号，而不是招募 β-arrestin 2与受体结合。我们的初步研究表明，SR-17018，我们最G偏向的化合物， 不会引起小鼠的呼吸抑制，尽管它在热板中具有与吗啡相同的效力 伤害感受测定。此外，与刺激小鼠跑步行为的吗啡不同，SR-17018不 引起过度活跃。当我们用SR-17018和吗啡治疗小鼠时，我们发现SR-17018阻断吗啡- 诱发多动症。我将继续使用β抑制蛋白的莫尔激动剂来表征行为反应 2-和G蛋白偏向的配体，以剂量反应的方式在自发活动测定和呼吸 抑制，以充分理解这种明显的竞争相互作用的性质。 该提案旨在获得行为和体外药理学方面的培训，以在莫尔定义阿片类药物相互作用 对小鼠我将获得行为研究的执行和设计，药代动力学数据采集， 和评估大脑区域的受体信号。此外，我的培训将需要获得理解， GPCR药理学原理的基础。我最初将使用药物强化的小鼠模型， 了解成瘾行为的训练将通过学习神经生物学的正式课程来加强 通过参与提案中概述的重点成瘾研究会议。研究 将用于确定辅助治疗的可能益处， 抗伤害，同时降低不良反应的风险。这些研究将揭示的作用， 小鼠中偏向激动作用的机制，以开发更安全的疼痛治疗和药物 并将为我提供培训，使我能够继续我的职业道路，成为一名独立的教师 成瘾科学研究员