Opioids, such as
morphine and
fentanyl, are widely used as effective
analgesics for the treatment of acute and
chronic pain. In addition, the
opioid system has a key role in the rewarding effects of
morphine,
ethanol,
cocaine and various other drugs. The authors have focused on
G-protein-activated inwardly rectifying
potassium (GIRK) channel subunits, GIRK2 and GIRK3, that are important molecules in
opioid transmission, and found that the single-nucleotide polymorphisms (SNPs) within the GIRK2 and GIRK3 gene regions were significantly associated with postoperative requirements of
analgesics including
opioids in patients who underwent abdominal surgery and
mRNA expression of these genes in postmortem specimens, one of which was also associated with vulnerability to
methamphetamine (METH) dependence. Further, by conducting a multistage genome-wide association study (GWAS) in healthy subjects, the authors found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative
opioid analgesics after painful cosmetic surgery. The C allele of the best candidate SNP, rs2952768, was associated with more
analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe
drug dependence in patients with
methamphetamine dependence, alcohol dependence, and
eating disorders and a lower 'Reward Dependence score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. The results show that SNPs in this locus are the most potent genetic factors associated with human
opioid sensitivity known to date, affecting both the efficacy of
opioid analgesics and liability to severe
substance dependence. These outcomes provide valuable information for the personalized treatment of
pain and
drug dependence.