Mu opioid receptors in pain management

Abstract

Most of the potent analgesics currently in use act through the mu opioid receptor. Although they are classified as mu opioids, clinical experience suggests differences among them. The relative potencies of the agents can vary from patient to patient, as well as the side-effect profiles. These observations, coupled with pharmacological approaches in preclinical models, led to the suggestion of multiple subtypes of mu receptors. The explosion in molecular biology has led to the identification of a single gene encoding mu opioid receptors. It now appears that this gene undergoes extensive splicing, in which a single gene can generate multiple proteins. Evidence now suggests that these splice variants may help explain the clinical variability in responses among patients.

Figure 1. Schematic of the human mu opioid receptor (OPRM1) gene structure and alternative splicing

A. Gene structure of the human OPRM1 gene. Exons and introns are showed by boxes and horizontal lines, respectively. Intron size is indicated below the introns as kilobases (kb). Promoters are showed by arrows. B. Alternatively spliced variants of the human OPRM1 gene. Exon composition for each alternatively spliced variant was showed by appropriate exon boxes. The lines between exons are introns that are spliced out during splicing. Translation start and stop points are shown by bars below and above exon boxes, respectively. From the literature.

Fig 2. Schematic of the human OPRM1 carboxyl terminal splice variants’ structures and amino acid sequences predicted from downstream exons of exon 3

The common receptor structure of all the human carboxyl terminal splice variants is indicated by heavy lines across the lipid bilayer of the cell membrane. Splice junctions between exons are indicated by arrows. The amino acid sequences predicted from different downstream exons are shown on the right along with the indicated splice variants. Potential phosphorylation sites are indicated by the italic letters and the following symbols on the top of the letters. △: cAMP- and cGMP-dependent protein kinase phosphorylation site; ○: tyrosine kinase phosphorylation site; *: casein kinase II phosphorylation site.