The OPRM1 gene contains a missense mutation in exon 1 that is one of the most heavily studied polymorphisms in the genetics of substance abuse; this polymorphism causes a A–G substitution at position 118 (rs1799971 a.k.a. A118G, N40D, and Asn40Asp) (Mague and Blendy 2010; Yuferov et al. 2010). Although several in vitro studies have suggested that this polymorphism has functional consequences (Kroslak et al. 2007), the direction of the effect has been disputed has been disputed. Early studies suggested that the minor (G) allele was associated with increased agonist affinity (gain-of-function), but more recent studies have suggested lower mRNA and protein expression (Beyer et al. 2004; Zhang et al. 2005), and lower receptor binding potential (Ray et al. 2011), suggesting a loss-of-function in G allele carriers. Associations have been published with many traits, including substance abuse and pain sensitivity, however, they remain controversial (Mague and Blendy. 2010; Yuferov et al. 2010; Walter and Lotsch 2009; Arias et al. 2006; Ray et al. 2011). To examine the effects of this polymorphism on behavior while maintaining an isogenic environmental and genetic background,
