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In vivo characterization of opioid biased agonists

阿片类偏向激动剂的体内表征

基本信息

批准号：
10062935
负责人：
JACK BERGMAN
金额：
$ 24.56万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062935
关键词：
Abstinence Abstinence Syndrome Acute Address Affinity Aftercare Agonist Air Analgesics Animals Atmosphere Attenuated Behavior Behavioral Biological Assay Carbon Dioxide Characteristics Chronic Clinical Constipation Coupling Data Dependence Development Dose Drug Prescriptions Equipment and supply inventories Female Fentanyl GTP-Binding Proteins Genes Goals Hypercapnia In Vitro Intake Knockout Mice Laboratories Ligands Malignant - descriptor Mental Depression Methods Monkeys Morphine Movement Mus Naltrexone National Institute of Drug Abuse Opiate Addiction Opioid Opioid Analgesics Opioid agonist Oxycodone Pain Performance Pharmaceutical Preparations Pharmacologic Substance Pharmacology Plethysmography Procedures Regimen Relapse Reporting Respiration Respiratory physiology Rice Safety Self Administration Sex Differences Signal Transduction Signaling Protein Tail Time Ventilatory Depression Water Withdrawal addiction appropriate dose arrestin 2 base beta-arrestin clinical practice drug seeking behavior experimental study improved in vivo male mu opioid receptors nonhuman primate novel novel therapeutics opioid epidemic optimism pre-clinical prescription opioid programs receptor recruit respiratory response sex side effect ventilation

项目摘要

OTHER PROJECT INFORMATION - SECTION 7 - PROJECT SUMMARY/ABSTRACT 1 The ongoing opioid crisis has led to renewed concerns about the clinical prescription of addictive opioid 2 analgesics. However, there currently are no suitable alternatives for treating severe or malignant pain. Studies 3 of opioid signaling mechanisms in mice lacking the β-arrestin 2 gene indicate that the acute analgesic effects 4 of morphine were enhanced in these mice, and subsequent studies reported that undesirable effects of 5 morphine including respiratory depression, constipation, and analgesic tolerance were all diminished in the 6 absence of β-arrestin signaling. These findings have led to increased efforts in developing novel opioid drugs 7 that, based on their preferential activation of G-protein signaling over β-arrestin signaling in vitro, can be 8 characterized as `biased' agonists. However, although clear distinctions in receptor-activated signaling of 9 opioid ligands are found in vitro, the extent to which these cellular differences predict differing profiles of opioid 10 activity in vivo remains uncertain. Currently, there is not sufficient information to conclude whether biased 11 signaling can indeed be associated with reduced opioid side effects and, consequently, an improved safety 12 profile of `biased' agonists compared to conventional prescription opioids. The present application intends to 13 address the need for preclinical data to rigorous evaluate this possibility with a program of in vivo studies of the 14 effects of novel opioid biased agonists in nonhuman primates. In these studies, we will employ well-established 15 and highly translational pharmacological methods to compare prescription opioids that are `balanced' agonists, 16 i.e., signal through both G-protein and β-arrestin paths (morphine, oxycodone, and fentanyl) with the `biased' 17 agonist PZM21 and two novel ligands that are provided by colleagues at the NIDA IRP and that, based on in 18 vitro data, also can be characterized as opioid `biased' agonists. First, the acute effects of different opioids will 19 be studied using well-validated assays of antinociception and operant performance, respiratory function, and 20 abuse potential. Data from these studies will enable us to rigorously characterize and compare both the 21 beneficial and unwanted effects of the `balanced' and `biased' agonists. Next, the same drugs will be compared 22 during regimens of chronic treatment. In these studies, assays of antinociception and operant performance will 23 be used to evaluate tolerance, defined by rightward or downward movement of the opioid dose-effect function, 24 and assays of respiratory function and observable behavior to evaluate the presence of opioid dependence, 25 evident as increases in ventilation or characteristic behavioral signs following antagonist administration. The 26 results of the latter studies will provide critical information regarding the dependence liability of `biased' 27 agonists that, in clinical practice, might be given on a repeated, or chronic, basis. Finally, cognizant of sex- 28 related differences in the effects of prescription opioids that are `balanced' agonists, we will conduct our studies 29 in both male and female subjects to determine whether similar sex-related differences are produced by novel 30 opioid `biased' agonists.

其他项目信息-第7节-项目摘要/摘要