ARR3 and respiratory depression: This push to develop ultra-G-biased ligands followed reports that Arr3-KO mice show increased analgesia (Bohn et al., 1999) and reduced tolerance (Bohn et al., 2000) and respiratory depression (Raehal et al., 2005) in response to morphine compared to WT mice, indicating that biased ligands could ameliorate these key side effects.