Biased signaling by endogenous opioid peptides

Significance There are >20 different endogenous opioid peptides derived from the three precursors proopiomelanocortin, proenkephalin, and prodynorphin; a long-standing question is the biological utility of having this variety of peptides. We addressed this question by systematically evaluating ligand binding and signaling properties of the peptides at each of the three opioid receptor types. Contrary to the prevailing notion, we show that all of the peptides bind and activate the three opioid receptors and that shorter β-endorphin peptides exhibit agonistic activity. Finally, we demonstrate that some endogenous peptides favor particular signaling pathways at the three receptors leading to biased signaling. These findings highlight the complexity of signaling where multiple opioid receptors are expressed and/or many opioid peptides are released.