title: Haplotypes of P2RX7 gene polymorphisms are associated with both cold pain sensitivity and analgesic effect of fentanyl.
abstract: BACKGROUND
  The P2X7 receptor is a member of the P2X family of adenosine 5'-triphosphate-gated cation channels. Several recent studies have demonstrated that this receptor is involved in mechanisms related to pain and inflammation. However, unknown is whether polymorphisms of the P2RX7 gene that encodes the human P2X7 receptor influence pain sensitivity and analgesic effects of opioids. The P2RX7 gene is known to be highly polymorphic. Thus, the present study examined associations between fentanyl sensitivity and polymorphisms in the P2RX7 gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery.
  
  
  RESULTS
  We first conducted linkage disequilibrium (LD) analyses for 55 reported single-nucleotide polymorphisms (SNPs) in the region within and around the P2RX7 gene using genomic samples from 100 patients. In our samples, 42 SNPs were polymorphic, and a total of five LD blocks with six Tag SNPs (rs2708092, rs1180012, rs1718125, rs208293, rs1718136, and rs7132846) were observed. Thus, we further analyzed associations between genotypes/haplotypes of these Tag SNPs and clinical data using a total of 355 samples. In the genotype-based association study, only the rs1718125 G>A SNP tended to be associated with higher pain scores on a visual analog scale 24 h after surgery (VAS24). The haplotype-based association study showed that subjects with homozygous haplotype No.3 (GTAAAC; estimated frequency: 15.0%) exhibited significantly higher cold pain sensitivity and lower analgesic effects of fentanyl for acute cold pain in the cold pressor test. Conversely, subjects who carried haplotype No.1 (ACGGAC; estimated frequency: 24.5%) tended to exhibit lower cold pain sensitivity and higher analgesic effects of fentanyl. Furthermore, subjects with homozygous haplotype No.2 (GCGGAC; estimated frequency: 22.9%) exhibited significantly lower VAS24 scores.
  
  
  CONCLUSIONS
  Cold pain sensitivity and analgesic effects of fentanyl were related to the SNP and haplotypes of the P2RX7 gene. The patients with the rs1718125 G>A SNP tended to show higher VAS24 scores. Moreover, the combination of polymorphisms from the 5'-flanking region to exon 5 recessively affected cold pain sensitivity and analgesic effects of opioids for acute cold pain. The present findings shed light on the involvement of P2RX7 gene polymorphisms in naive cold pain sensitivity and analgesic effects of fentanyl.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ide
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nishizawa
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Shinya
authors.initials: S
authors.lastname: Kasai
authors.forename: Junko
authors.initials: J
authors.lastname: Hasegawa
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hayashida
authors.forename: Masabumi
authors.initials: M
authors.lastname: Minami
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. ikeda-kz@igakuken.or.jp.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000328:Adult; D000700:Analgesics / Q000494:pharmacology; D002412:Cations; D003080:Cold Temperature; D005260:Female; D005283:Fentanyl / Q000494:pharmacology*; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D010146:Pain / Q000235:genetics*; D059408:Pain Management / Q000379:methods; D017288:Pain Threshold / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D058486:Receptors, Purinergic P2X7 / Q000235:genetics*; D055815:Young Adult
chemical_list: D000700:Analgesics; D002412:Cations; D007473:Ion Channels; C546468:P2RX7 protein, human; D058486:Receptors, Purinergic P2X7; D005283:Fentanyl