Nishizawa Daisuke, Ikeda Kazutaka
Nihon Arukoru Yakubutsu Igakkai Zasshi. 2014 Apr;49(2):83-91.
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.
阿片类药物，如吗啡和芬太尼，被广泛用作治疗急慢性疼痛的有效镇痛药。此外，阿片系统在吗啡、乙醇、可卡因和其他各种药物的奖赏效应中起关键作用。作者聚焦于G蛋白激活内向整流钾通道（GIRK）亚基GIRK2和GIRK3，它们是阿片传递中的重要分子，并发现GIRK2和GIRK3基因区域内的单核苷酸多态性（SNP）与接受腹部手术患者术后包括阿片类药物在内的镇痛药需求以及死后标本中这些基因的mRNA表达显著相关，其中一个还与甲基苯丙胺（METH）依赖易感性相关。此外，通过在健康受试者中进行多阶段全基因组关联研究（GWAS），作者发现跨越2q33.3 - 2q34的连锁不平衡区域内的基因多态性与美容整形手术后阿片类镇痛药的需求密切相关。最佳候选SNP rs2952768的C等位基因与更多的镇痛需求相关，并且在接受腹部手术的患者中也得到了一致的结果。此外，该SNP中C等位基因的携带者在甲基苯丙胺依赖、酒精依赖和饮食失调患者中对严重药物依赖的易感性较低，在健康受试者的人格问卷中“奖赏依赖”得分也较低。此外，该SNP的C/C基因型与邻近基因CREB1的表达升高显著相关。结果表明，该位点的SNP是迄今为止已知的与人类阿片敏感性最相关的遗传因素，影响阿片类镇痛药的疗效和严重物质依赖的易感性。这些结果为疼痛和药物依赖的个性化治疗提供了有价值的信息。
