Human genetic studies suggest that OPRM1 (encodes MOR) gene variants play key roles in susceptibility to opioid addiction in humans. Most prominently, an A118G single nucleotide polymorphism (SNP) in OPRM1, rs1799971, is a non-synonymous gene variant which replaces asparagine at position 40 (N40) with aspartate (D40), occurs at a frequency of ~3% in African, 39-42% in Asian and ~16% in European ancestry 5, and is associated with drug dependence phenotypes 6, 7. There have been numerous investigations into the functional consequences of the MOR D40 variant on receptor activation in overexpression models or knock-in models with mouse, primates, and humans 6, 8–16. Importantly, human clinical studies found that MOR A118G alters hypothalamic-pituitary-adrenal (HPA) axis activation, and human subjects (of both sexes) harboring A118G-allelilc variants were shown to have a relatively greater tonic inhibition at HPA sites through the MOR 17, 18. In addition, monkeys carrying OPRM1 C77G SNP (thought to be analogous to A118G, but not on A118G per se) demonstrated a higher MOR affinity to β-endorphin and significantly lower basal adrenocorticotropic hormone (ACTH) stimulated plasma cortisol levels associated with
