气候变化领域集成服务门户(CCPortal): Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects

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DOI	10.1073/pnas.2000017118
	Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects
	Kandasamy R.; Hillhouse T.M.; Livingston K.E.; Kochan K.E.; Meurice C.; Eans S.O.; Li M.-H.; White A.D.; Roques B.P.; McLaughlin J.P.; Ingram S.L.; Burford N.T.; Alt A.; Traynor J.R.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Allostery; Analgesia; Endogenous opioid peptides; Mu-opioid receptor; Signaling bias
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179820
作者单位	Edward F. Domino Research Center, Department of Pharmacology, University of Michigan, Medical School, Ann Arbor, MI 48109, United States; Department of Psychology, California State University, East Bay, Hayward, CA 94542, United States; Department of Psychology, University of Wisconsin-Green Bay, Green Bay, WI 54311, United States; Department of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville, FL 32610, United States; Department of Neurological Surgery, Oregon Health and Science University, Portland, OR 97239, United States; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States; Unité de Technologies Chimiques et Biologiques pour la Santé, Université Paris Descartes, Paris, Cedex 05, France; Lead Discovery and Optimization, Bristol-Myers Squibb, Wallingford, CT 06492, United States; Center for Chemical Genomics, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, United States
推荐引用方式 GB/T 7714	Kandasamy R.,Hillhouse T.M.,Livingston K.E.,et al. Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects[J],2021,118(16).
APA	Kandasamy R..,Hillhouse T.M..,Livingston K.E..,Kochan K.E..,Meurice C..,...&Traynor J.R..(2021).Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Kandasamy R.,et al."Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).