Initial studies demonstrated that the Asp40 variant increases the binding affinity of β endorphin to 3-fold higher than that of the Asn40 human mu opioid receptor (hMOR) in AV-12 cells and results in higher potency for the activation of G protein-coupled potassium channels (Bond et al., 1998). Other studies reported no differences in agonist binding, functional coupling, or desensitization (Befort et al., 2001; Beyer et al., 2004). Using an allelic expression assay, Zhang and colleagues (2005) found a 1.5-fold reduction in allele-specific mRNA expression and a 10-fold reduction in protein levels with the Asp40. More recent data supported this claim, showing lower surface receptor expression, decreased forskolin-induced cyclic AMP activation, and lower agonist-induced MOR activation with the Asp40 allele (Kroslak et al., 2007). Discrepancies in the in vitro findings establish the rationale for generating a mouse model to examine the pharmacological, molecular, and behavioral significance of this polymorphism. A knock-in mouse model harboring the equivalent point mutation in the mouse, the A112G, which alters the same amino acid coding from an asparagine to aspartic acid at position 38 (Asn38Asp; N38D),
