Papers of the Week

G protein-coupled receptors can signal through both G proteins and ß-arrestin2. For the μ-opioid receptor, early experimental evidence from a single study suggested that G protein signalling mediates analgesia whereas ß-arrestin2 signalling mediates respiratory depression and constipation. Consequently, for more than a decade much research effort has been focused on developing biased μ-opioid agonists that preferentially target G protein signalling over β-arrestin signalling as it was believed that such drugs would be analgesics devoid of respiratory depressant activity. However, the prototypical compounds that have been developed based on this concept have so far failed in clinical and preclinical development.