title: Association between KCNJ6 (GIRK2) gene polymorphisms and postoperative analgesic requirements after major abdominal surgery.
abstract: Opioids are commonly used as effective analgesics for the treatment of acute and chronic pain. However, considerable individual differences have been widely observed in sensitivity to opioid analgesics. We focused on a G-protein-activated inwardly rectifying potassium (GIRK) channel subunit, GIRK2, that is an important molecule in opioid transmission. In our initial polymorphism search, a total of nine single-nucleotide polymorphisms (SNPs) were identified in the whole exon, 5'-flanking, and exon-intron boundary regions of the KCNJ6 gene encoding GIRK2. Among them, G-1250A and A1032G were selected as representative SNPs for further association studies. In an association study of 129 subjects who underwent major open abdominal surgery, the A/A genotype in the A1032G SNP and -1250G/1032A haplotype were significantly associated with increased postoperative analgesic requirements compared with other genotypes and haplotypes. The total dose (mean+/-SEM) of rescue analgesics converted to equivalent oral morphine doses was 20.45+/-9.27 mg, 10.84+/-2.24 mg, and 13.07+/-2.39 mg for the A/A, A/G, and G/G genotypes in the A1032G SNP, respectively. Additionally, KCNJ6 gene expression levels in the 1032A/A subjects were significantly decreased compared with the 1032A/G and 1032G/G subjects in a real-time quantitative PCR analysis using human brain tissues, suggesting that the 1032A/A subjects required more analgesics because of lower KCNJ6 gene expression levels and consequently insufficient analgesic effects. The results indicate that the A1032G SNP and G-1250A/A1032G haplotype could serve as markers that predict increased analgesic requirements. Our findings will provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.
authors.affiliation: Division of Psychobiology, Tokyo Institute of Psychiatry, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nishizawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Nagashima
authors.forename: Ryoji
authors.initials: R
authors.lastname: Katoh
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Satoh
authors.forename: Megumi
authors.initials: M
authors.lastname: Tagami
authors.forename: Shinya
authors.initials: S
authors.lastname: Kasai
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Ogai
authors.forename: Wenhua
authors.initials: W
authors.lastname: Han
authors.forename: Junko
authors.initials: J
authors.lastname: Hasegawa
authors.forename: Naohito
authors.initials: N
authors.lastname: Shimoyama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hayashida
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000005:Abdomen / Q000601:surgery*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics / Q000494:pharmacology*; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000494:pharmacology; D010146:Pain / Q000235:genetics*; D010147:Pain Measurement; D010149:Postoperative Pain / Q000188:drug therapy*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000700:Analgesics; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C094401:KCNJ6 protein, human; D009020:Morphine