To understand how the newly identified SNP may produce functional effects, we constructed a reporter vector that includes the entire predicted IRES element. Although the exact molecular mechanism by which rs563649 regulates OPRM1 function and pain signaling requires further studies, out data suggest that the presence of minor T allele should lead to higher expression levels of corresponding MOR-1K isoforms. Furthermore, the localization of a strong functional SNP within the human analog of mouse exon 13 provides evidence for the biological significance of MOR-1K isoforms. We showed that MOR-1K isoforms with variable exon 13–exon 2 junctions are expressed in a tissue-specific manner and likely contribute to tissue-specific post-transcriptional regulation. Because the T allele of rs563649 is associated with higher translation efficiency and higher pain sensitivity, we suggest that the truncated MOR-1K form contributes to hyperalgesic-like rather than analgesic states and plausibly represents one of the molecular mechanisms underlying the excitatory effect of opiods, contributing to tolerance, drug dependence and opioid-induced hyperalgesia (60–62). Furthermore, similarities in the tissue-specific expression patterns between MOR-1 and MOR-1K, with lower abundance of MOR-1K relative to
