Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants

Cell Mol Neurobiol. 2021 Jul;41(5):1039-1055. doi: 10.1007/s10571-020-00971-7. Epub 2020 Oct 3.


The opioid receptor (OPR) family comprises the mu-, delta-, and kappa-opioid, and nociceptin receptors that belong to the superfamily of 7-transmembrane spanning G protein-coupled receptors (GPCRs). The mu-opioid receptor is the main target for clinically used opioid analgesics, and its biology has been extensively studied. The N-terminally truncated 6TM receptors isoform produced through alternative splicing of the OPRM1 gene displays unique signaling and analgesic properties, but it is unclear if other OPRs have the same ability. In this study, we have built a comprehensive map of alternative splicing events that produce 6TM receptor variants in all the OPRs and demonstrated their evolutionary conservation. We then obtained evidence for their translation through ribosomal footprint analysis. We discovered that N-terminally truncated 6TM GPCRs are rare in the human genome and OPRs are overrepresented in this group. Finally, we also observed a significant enrichment of 6TM GPCR genes among genes associated with pain, psychiatric disorders, and addiction. Understanding the biology of 6TM receptors and leveraging this knowledge for drug development should pave the way for novel therapies.

Keywords: Alternative splicing; Evolutionary conservation; Gene enrichment; Opioid receptor.

MeSH terms

  • Alternative Splicing / genetics*
  • Animals
  • Cell Line, Tumor
  • Conserved Sequence / genetics*
  • Databases, Genetic
  • Genetic Variation / genetics
  • Humans
  • Macaca
  • Mice
  • Nociceptin Receptor
  • Receptors, Opioid / genetics*
  • Receptors, Opioid, delta / genetics*
  • Receptors, Opioid, kappa / genetics*
  • Receptors, Opioid, mu / genetics*
  • Species Specificity


  • OPRD1 protein, human
  • OPRK1 protein, human
  • OPRM1 protein, human
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Nociceptin Receptor