Papers of the Week

SignificanceTransmembrane signaling through G protein-coupled receptors (GPCRs), originally described as requiring coupling to intracellular G proteins, also uses G protein-independent pathways through β-arrestin recruitment. Biased ligands, by favoring one of the multiple bioactive conformations of GPCRs, allow selective signaling through either of these pathways. Here, we identified Serodolin as the first β-arrestin-biased agonist of the serotonin 5-HT receptor. This new ligand, while acting as an inverse agonist on G signaling, selectively induces ERK activation in a β-arrestin-dependent way. Importantly, we report that Serodolin decreases pain intensity caused by thermal, mechanical, or inflammatory stimuli. Our findings suggest that targeting the 5-HTR with β-arrestin-biased ligand could be a valid alternative strategy to the use of opioids for the relief of pain.