A Non-Synonymous Single Nucleotide Polymorphism in an OPRM1 Splice Variant Is Associated with Fentanyl-Induced Emesis in Women Undergoing Minor Gynaecological Surgery

Abstract

BackgroundFentanyl-induced emesis (FIE) is a distressing adverse effect in the postoperative setting. The genetic basis of FIE remains largely unknown, therefore, we examined whether it was associated with specific genetic variants of OPRM1, the gene encoding the main receptor target of fentanyl.MethodsIn this prospective case-control study, 193 women undergoing gynaecological surgery under a standardized anaesthetic with a low emetogenic risk were enrolled. Inclusion and exclusion criteria were designed to select extreme phenotypes as well as to ensure that most major confounders for FIE were either excluded or present in all patients. To control for unforeseen intra- and postoperative confounders for FIE, only 161 patients were further analysed, out of which 10 were categorized as having FIE, defined by the presence of at least one of three symptoms: nausea, vomiting or retching that was likely to be fentanyl-related. To identify SNPs relevant to FIE in our population, DNA from 40 controls and 10 cases was sequenced at the following OPRM1 regions: 3 kbp of the promoter, main and alternative exons as well as 2 kbp of the 3′ downstream region. The genotype of the significant SNP was further determined in the remaining 111 controls.ResultsThe incidence of FIE was 6.2%. Initial sequencing of 10 cases and 40 controls identified 25 SNPs. Only rs540825, a non-synonymous SNP in the splice variant, MOR1X, showed a significant association with FIE post-Bonferroni correction. This SNP was further examined in the remaining 111 controls which confirmed its significant association with FIE (p = 0.019 post-Bonferroni, OR: 5.6, 95% CI: 1.42–21.91).ConclusionsThis is the first report of an association between the occurrence of FIE in Chinese women undergoing gynaecological surgery and an OPRM1 splice variant SNP, rs540825.

Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting

“…As expected, there are consistent associations with SNPs (single nucleotide polymorphisms) occurring in genes involving neural signaling and transmitter receptors in the nausea and vomiting system (Table 1). SNPs for 5-HT 3 (subunits A and B), muscarinic type 3, and μ opioid receptors are associated with PONV and OINV (Chou et al, 2006; Janicki et al, 2011; Kolesnikov et al, 2011; Laugsand et al, 2011; Pang et al, 2012; Rueffert et al, 2009; Sia et al, 2008; Zhang et al, 2011). SNPs for dopamine type 2 receptors are also related to PONV (Nakagawa et al, 2008).…”

Regulation and Functional Implications of Opioid Receptor Splicing in Opioid Pharmacology and HIV Pathogenesis

“…Furthermore, these isoforms, in conjunction with several SNPs, are understood to have important physiological signifigance in opioid sensitivity and addiction (Klein et al, 2009; Kreek and LaForge, 2007; Lotsch and Geisslinger, 2005), as some polymorphisms in the MOR-1K (Diatchenko et al, 2011; Shabalina et al, 2009) and MOR-1X (Pang et al, 2012) variants have been found to alter opioid drug response, while others have not (Mayer and Hollt, 2006; Smith et al, 2005). Therefore, opioid receptor isoforms must be regarded as a separate receptor subtype that collectively contributes to the overall cellular and physiological effects of opioids and differential expression of these isoforms will alter opioid pharmacology accordingly.…”

“…The recent identification and characterization of several opioid receptor isoforms generated through alternative splicing of opioid receptor-encoding genes, particularly the m-opioid receptor-encoding OPRM1, has led to a more conclusive explanation for the discrepancies observed in opioid pharmacology, as structural differences between isoforms result in unique agonist selectivity, constitutive activity, agonistmediated signaling, and internalization. Furthermore, these isoforms, in conjunction with several SNPs, are understood to have important physiological signifigance in opioid sensitivity and addiction (Lotsch and Geisslinger, 2005;Kreek and LaForge, 2007;Klein et al, 2009), as some polymorphisms in the MOR-1K (Shabalina et al, 2009;Diatchenko et al, 2011) and MOR-1X (Pang et al, 2012) variants have been found to alter opioid drug response, while others have not (Smith et al, 2005;Mayer and Hollt, 2006). Therefore, opioid receptor isoforms must be regarded as separate receptor subtypes that collectively contribute to the overall cellular and physiological effects of opioids and differential expression of these isoforms will alter opioid pharmacology accordingly.…”

Splice variation of the mu-opioid receptor and its effect on the action of opioids

“…Results have shown an association between a SNP in the splice variant, MOR1X, and occurrence of fentanyl-induced emesis in the postoperative setting. 52 Furthermore, in a model of mice with 'morphineinduced scratching' (MIS), researchers propose that a MOR variant, MOR1D, is essential for MIS, whereas the major protein transcript of OPRM, MOR1, is necessary for mediating analgesia and that these processes may be independent of each other. 53 …”

“…Results have shown an association between a SNP in the splice variant, MOR1X, and occurrence of fentanyl-induced emesis in the postoperative setting. 52…”