Abstract
The mu opioid receptor has a distinct place in the opioid receptor family, since it mediates the actions of most opioids used clinically (e.g., morphine and fentanyl), as well as drugs of abuse (e.g., heroin). The single-copy mu opioid receptor gene, OPRM1, goes through extensive alternative pre-mRNA splicing to generate numerous splice variants that are conserved from rodents to humans. These OPRM1 splice variants can be classified into three structurally distinct types: (1) full-length 7 transmembrane (TM) carboxyl (C)-terminal variants; (2) truncated 6TM variants; and (3) single TM variants. Distinct pharmacological functions of these splice variants have been demonstrated by both in vitro and in vivo studies, particularly by using several unique gene-targeted mouse models. These studies provide new insights into our understanding of the complex actions of mu opioids with regard to OPRM1 alternative splicing. This review provides an overview of the studies that used these gene-targeted mouse models for exploring the functional importance of Oprm1 splice variants.
Highlights
Mu opioids, including those derived from opium, such as morphine, and synthetic ones such as fentanyl and methadone, remain in the mainstream for severe pain management in the clinic despite their side-effects such as tolerance, physical dependence, addiction, constipation, pruritus, and respiratory depression
This review mainly focuses on the generation of these gene-targeted mouse models, their application in exploring the in vivo functions of Oprm1 splice variants, and what we have learned from these studies
Extensive alternative splicing of the single-copy OPRM1 gene generates an array of splice variants, providing molecular diversity and complexity that is exceptional within the opioid receptor family and in G-protein coupled receptor (GPCR)
Summary
Mu opioids, including those derived from opium, such as morphine, and synthetic ones such as fentanyl and methadone, remain in the mainstream for severe pain management in the clinic despite their side-effects such as tolerance, physical dependence, addiction, constipation, pruritus, and respiratory depression Misusing these mu opioids can magnify their side-effects and promote the development of opioid use disorder, a main cause of the worldwide opioid epidemic and opioid overdose deaths, which have been climbing steeply in the United States in recent years [1]. The functional relevance of these OPRM1 splice variants in mu opioid pharmacology has been demonstrated by both in vitro and in vivo studies, by using gene-targeted mouse models. This review mainly focuses on the generation of these gene-targeted mouse models, their application in exploring the in vivo functions of Oprm splice variants, and what we have learned from these studies
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