Exploring Pharmacological Functions of Alternatively Spliced Variants of the Mu Opioid Receptor Gene, Oprm1, via Gene-Targeted Animal Models

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.

A Balancing Act: Learning from the Past to Build a Future-Focused Opioid Strategy

“…The efficacies of morphine and DAMGO are equivalent for both activation of GIRK channels and inhibition of transmitter release in the VTA ( 65 ). Furthermore, the 22-amino-acid substitution is entirely contained within exon 3, meaning any putative MOR splice variants ( 74 ) that alter their endocytosis ( 75 ) also carry this new GRK barcode. Although we cannot rule out that the RMOR, but not the wild-type MOR, signals to an unidentified effector specific to DORs to protect against tolerance, dependence, and compulsive drug seeking, this seems unlikely, as deletion of the DOR actually reduces tolerance to morphine ( 76 ).…”