Following the discovery that β-arrestin knockout (KO) animals treated with morphine showed enhanced antinociception with decreased respiratory depression and constipation53, the “arrestin hypothesis” or the idea that β-arrestin mediates adverse side effects of MOR activation further motivated the academic field and industry to design G-protein-biased MOR agonists or drugs that would activate β-arrestin less than the G-protein pathway (Figure 2)27. Here, SAG is linked to respiratory depression.