Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside?

Elisa Mura,¹ Stefano Govoni,¹ Marco Racchi,¹ Valeria Carossa,¹ Guglielmina Nadia Ranzani,² Massimo Allegri,^3,4 Ron HN van Schaik<sup>5

1</sup>Department of Drug Sciences, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy; ²Department of Biology and Biotechnology, University of Pavia, Pavia, Italy; ³Pain Therapy Service, Foundation IRCCS San Matteo Hospital, Pavia, Italy; ⁴Department of Clinical, Surgical Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; ⁵Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands

Abstract: The 118A>G single nucleotide polymorphism (SNP) in the µ-opioid receptor (OPRM1) gene has been the most described variant in pharmacogenetic studies regarding opioid drugs. Despite evidence for an altered biological function encoded by this variant, this knowledge is not yet utilized clinically. The aim of the present review was to collect and discuss the available information on the 118A>G SNP in the OPRM1 gene, at the molecular level and in its clinical manifestations. In vitro biochemical and molecular assays have shown that the variant receptor has higher binding affinity for ß-endorphins, that it has altered signal transduction cascade, and that it has a lower expression compared with wild-type OPRM1. Studies using animal models for 118A>G have revealed a double effect of the variant receptor, with an apparent gain of function with respect to the response to endogenous opioids but a loss of function with exogenous administered opioid drugs. Although patients with this variant have shown a lower pain threshold and a higher drug consumption in order to achieve the analgesic effect, clinical experiences have demonstrated that patients carrying the variant allele are not affected by the increased opioid consumption in terms of side effects.

Keywords: µ-opioid receptor, opioids, pharmacogenetics, pain, analgesia