Here we show that almost all of the known mouse exons have corresponding orthologs within the human OPRM1 gene locus and can be subject to genetic variability, which modifies receptor function and associated phenotypes. Association analysis of human allelic variations within these new exons with quantitative measures of pain sensitivity and responses to morphine identified a novel and potentially functional SNPs in the human OPRM1 gene. Furthermore, we cloned new human MOR-1K isoforms that carry SNP rs563649, which is strongly associated with pain-sensitivity phenotypes. We demonstrated that SNP rs563649 is located within a structurally conserved internal ribosome entry site (IRES) in the 5′-UTR of these novel isoforms and affects translational efficiency of these variants. Our results substantially extend our knowledge of the OPRM1 gene locus and introduce new targets for the development of genetic markers, which may lead to individualized opioid-based therapies.
