OPRM1 and respiratory depression: Unexpectedly, the novel macrocyclic tetrapeptide [Nal(2′)4]CJ-15,208 demonstrated bifunctional MOR agonism and DOR-selective antagonism, producing antinociception in the mouse 55 °C warm-water tail-withdrawal assay without the clinical liabilities associated with standard MOR agonists, namely tolerance, respiratory depression, or psychostimulation, and lacked rewarding properties in a conditioned place preference paradigm.