Biased Agonism: Lessons from Studies of Opioid Receptor Agonists

In ligand bias different agonist drugs are thought to produce distinct signaling outputs when activating the same receptor. If these signaling outputs mediate therapeutic versus adverse drug effects, then agonists that selectively activate the therapeutic signaling pathway would be extremely beneficial. It has long been thought that mu-opioid receptor agonists that selectively activate G protein- over beta-arrestin-dependent signaling pathways would produce effective analgesia without the adverse effects such as respiratory depression. However, more recent data indicate that most of the therapeutic and adverse effects of agonist-induced activation of the mu-opioid receptor are actually mediated by the G protein-dependent signaling pathway, and that a number of drugs described as G protein biased in fact may not be biased, but instead may be low-intrinsic-efficacy agonists. In this review we discuss the current state of the field of bias at the mu-opioid receptor and other opioid receptor subtypes.

Automated summary

In ligand bias, different agonist drugs activate distinct signaling pathways, leading to different therapeutic and adverse effects. While it was believed that selectively activating the G protein-dependent pathway of the mu-opioid receptor would result in effective analgesia without adverse effects, recent data suggest that most effects are mediated by this pathway and some drugs described as biased may actually be low-intrinsic-efficacy agonists. This review discusses the current understanding of bias at the mu-opioid receptor and other opioid receptor subtypes.