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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要我们实验室的重点是了解不同配体如何调节 mu 阿片受体的活性（MOR）以及差异激活如何保持或防止通常由为此，博恩实验室致力于开发不同的“偏向”激动剂。吗啡和脑啡肽通过 G 蛋白途径优先发出信号而不是招募信号的能力我们的初步研究表明，我们最偏向 G 的化合物 SR-17018 确实如此。尽管它与热板中的吗啡具有相同的效力，但不会引起小鼠呼吸抑制此外，与刺激小鼠奔跑行为的吗啡不同，SR-17018 不会刺激小鼠奔跑行为。当我们用 SR-17018 和吗啡治疗小鼠时，我们发现 SR-17018 会阻断吗啡- 我将继续使用 βarrestin 的 MOR 激动剂来描述行为反应。 2-和G蛋白偏向配体，在运动活性测定和呼吸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本质。该提案旨在获得行为和体外药理学方面的培训，以定义 MOR 的阿片类药物相互作用我将在小鼠中获得执行和设计行为研究、获取药代动力学数据的培训，此外，我的培训将需要获得对大脑区域受体信号传导的理解。 GPCR 药理学原理的基础知识我将首先使用我的药物强化小鼠模型；通过参加神经生物学的正式课程，将加强理解成瘾行为的培训成瘾问题并参加提案中概述的重点成瘾研究会议。该应用的结果将用于确定辅助治疗的可能益处，以增强这些研究将阐明其作用和作用。小鼠偏向激动机制，致力于开发更安全的疼痛治疗和药物并将为我提供继续我的职业道路成为一名独立教师所需的培训成瘾科学研究人员。