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 aggression16. Bioinformatic analyses and animal studies reveal that the N40D substitution likely destroys an N’-terminal glycosylation site and reduces the surface expression of MORs 19–21. Nevertheless, another study using a humanized mouse model of N40D (i.e., the first exon of mouse OPRM1 was replaced with the first of human OPRM1 harboring N40D) is not in total agreement with this finding 22. Thus, understanding how the D40 variant affects MOR signaling and synaptic function when expressed at normal levels in human neurons may provide insight into mechanisms underlying drug abuse, at least in people carrying this variant.
