Opioid drugs are among the most commonly used and effective human analgesics. To date, the clinical benefits of opioid analgesics have not been fully realized due to substantial individual variations in the responses to opioids, insufficient drug dosing, and a high rate (up to 66%) of adverse events. As such, there is a substantial need to identify the genetic and molecular biological mechanisms that mediate individual responses to opioid therapy. Recent discoveries show that genetic variations in the μ-opioid receptor (OPRM1) gene locus play an essential role in inter-individual responses. The majority of genetic association studies have focused on the A118G polymorphism, which codes for a non-synonymous change in OPRM1 exon 1. In addition to the A118G polymorphism, another functional SNP (rs563649), which is located within an alternatively-spliced OPRM1 isoform (MOR-1K), has been identified. The MOR-1k isoform codes for 6TM OPRM1 isoforms that display excitatory rather than the inhibitory cellular effects, which are characteristic of the canonical 7TM isoforms. Thus, stimulation of the 6TM isoforms may engage the molecular mechanisms mediating opioid-dependent hyperalgesia, tolerance and dependence. Future clinical and basic studies that seek to identify the functional genetic variants within OPRM1 locus, and associated molecular mechanisms, will result in a better understanding of individual responses to opioid therapy and ultimately to the development new pharmacotherapeutics and diagnostic tools.
Conflict of interest statement
Authors declare no conflict of interests.
Expansion of the human mu-opioid receptor gene architecture: novel functional variants.Hum Mol Genet. 2009 Mar 15;18(6):1037-51. doi: 10.1093/hmg/ddn439. Epub 2008 Dec 22. Hum Mol Genet. 2009. PMID: 19103668 Free PMC article.
Identification of five mouse mu-opioid receptor (MOR) gene (Oprm1) splice variants containing a newly identified alternatively spliced exon.Gene. 2007 Jun 15;395(1-2):98-107. doi: 10.1016/j.gene.2007.02.004. Epub 2007 Feb 20. Gene. 2007. PMID: 17398041 Free PMC article.
A novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism.Mol Pain. 2010 Jun 2;6:33. doi: 10.1186/1744-8069-6-33. Mol Pain. 2010. PMID: 20525224 Free PMC article.
μ-Opioid receptor 6-transmembrane isoform: A potential therapeutic target for new effective opioids.Prog Neuropsychopharmacol Biol Psychiatry. 2015 Oct 1;62:61-7. doi: 10.1016/j.pnpbp.2014.11.009. Epub 2014 Dec 6. Prog Neuropsychopharmacol Biol Psychiatry. 2015. PMID: 25485963 Free PMC article. Review.
Cellular signalling of non-synonymous single-nucleotide polymorphisms of the human μ-opioid receptor (OPRM1).Br J Pharmacol. 2015 Jan;172(2):349-63. doi: 10.1111/bph.12644. Epub 2014 Jul 1. Br J Pharmacol. 2015. PMID: 24527749 Free PMC article. Review.
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