Alternative Pre-mRNA Splicing of the Mu Opioid Receptor Gene, OPRM1: Insight into Complex Mu Opioid Actions

Abstract

Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, creating multiple splice variants or isoforms via a variety of alternative splicing events. These OPRM1 splice variants can be categorized into three major types based on the receptor structure: (1) full-length 7 transmembrane (TM) C-terminal variants; (2) truncated 6TM; and (3) single TM variants. Increasing evidence suggests that these OPRM1 splice variants are pharmacologically important in mediating the distinct actions of various mu opioids. More importantly, the OPRM1 variants can be targeted for development of novel opioid analgesics that are potent against multiple types of pain, but devoid of many side-effects associated with traditional opiates. In this review, we provide an overview of OPRM1 alternative splicing and its functional relevance in opioid pharmacology.

Differential Effects on the Translation of Immune-Related Alternatively Polyadenylated mRNAs in Melanoma and T Cells by eIF4A Inhibition

“…More generally, many genes were recently described to have alternatively polyadenylated mRNA variants in human immune cells [ 27 ]. With the exception of a few genes [ 28 , 29 , 30 ], the differential functions of protein isoforms encoded by alternatively polyadenylated mRNAs are poorly documented. Here, we evaluated the effect of inhibiting eIF4A with silvestrol on the translation of alternatively polyadenylated mRNA isoforms in both melanoma and T cells.…”

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

“…One hypothesis to address this question is that multiple mu opioid receptors can be generated from the single copy of the OPRM1 gene through alternative splicing, a post-transcriptional event that provides transcriptomic and proteomic diversity in metazoan organisms. Over the past few decades, numerous OPRM1 splice variants have been isolated by several laboratories [ 8 , 9 , 11 ], proving that the hypothesis is correct. Although the association of these OPRM1 splice variants with the mu subtypes defined by the early pharmacological studies remains unclear, identification and characterization of these OPRM1 splice variants have revolutionized the concept of multiple mu opioid receptors and provided new insight into our understanding of the complex actions of mu opioids [ 9 , 11 , 12 ].…”

“…Over the past few decades, numerous OPRM1 splice variants have been isolated by several laboratories [ 8 , 9 , 11 ], proving that the hypothesis is correct. Although the association of these OPRM1 splice variants with the mu subtypes defined by the early pharmacological studies remains unclear, identification and characterization of these OPRM1 splice variants have revolutionized the concept of multiple mu opioid receptors and provided new insight into our understanding of the complex actions of mu opioids [ 9 , 11 , 12 ].…”

“…Soon after MOR-1 cDNA was cloned, the genomic structure of the OPRM1 gene with four exons and three introns was determined. Identification of additional 5′ and 3′ exons further expanded the length of the OPRM1 gene to over 200 kb ( Figure 1 ) [ 9 , 11 ]. The OPRM1 gene utilizes various splicing mechanisms to produce the multiple splice variants that can be classified into three types, the full-length 7TM C-terminal variants, the truncated 6TM variants, and 1TM variants.…”

“…The actions of these mu opioids are primarily mediated through the mu opioid receptor, a G-protein coupled receptor (GPCR) belonging to the class A rhodopsin family. The concept of multiple mu opioid receptors was initially proposed by early pharmacological studies [ 2 , 3 , 4 , 5 , 6 , 7 ] and further supported by identifying an array of alternatively spliced variants from a single-copy mu opioid receptor gene, OPRM1 [ 8 , 9 , 10 , 11 , 12 , 13 ].…”