studies. Several studies have demonstrated a relationship between the frequencies of the A118G OPRM1 genomic polymorphisms and OPRM1-dependent phenotypes, including responses to opiates (22–25) and variations in pressure pain thresholds (26). However, only a small percentage of the variability of related phenotypes has been explained and conflicting and/or inconsistent results have been reported (27). Furthermore, investigations of the functional properties of the 40Asn variant have produced inconsistent results. First, the minor G allele has been reported to increase the affinity of OPRM1 receptor variant for β-endorphin by 3-fold in AV-12 cells and Xenopus oocytes (28). Other studies have shown no differences in agonist binding, functional coupling and internalization between transiently expressed receptor variants and wild-type receptors in COS and HEK293 cells (29,30). Additionally, even though the original findings demonstrated greater functional activity of the G allele receptor variant, a substantial reduction in the expression of the variant allele at both RNA levels in human autopsy brain tissues and RNA and protein levels in the stably transfected cell lines has also been reported (30,31). Collectively, our current understanding of the genetic basis for individual variations in opioids responses suggests a strong contribution of other untested variables that may include genetic variants
