In this study, we performed an extensive search for functional SNPs within the OPRM1 gene locus and made several fundamental observations. First, we identified several novel and potentially functional SNPs. Particularly, a novel SNP rs563649, which is situated within the newly identified exon 13, was the strongest independent contributor to measured pain-sensitivity responses (Table 3). In contrast to SNP rs563649, the SNPs that have been previously associated with OPRM1-dependent phenotypes displayed rather modest effects. Specifically, the non-synonymous SNP variant A118G (Asp40Asn), which has been shown to be associated with human pressure pain thresholds (26), showed much smaller differences. In agreement with previous findings, in our cohorts homozygotes for the G allele displayed the highest mean values for mechanical pain thresholds, whereas homozygotes for the A allele displayed the lowest mean values for mechanical pain thresholds; however, this difference did not reach significance (data not shown). Importantly, the previously published association achieved statistical significance only among males (26), whereas our cohort tested for experimental pressure pain consisted of females only.
