How does biased agonism at the mu (μ) opioid receptor offer potential advantages in pain management?

Biased agonism at the mu (μ) opioid receptor offers potential advantages in pain management by selectively activating specific downstream signaling pathways while avoiding others that contribute to adverse effects. Traditionally, it was thought that a ligand (drug) either activated or inhibited a receptor, leading to a single set of downstream effects. However, biased agonism reveals that different ligands can stabilize different receptor conformations, leading to the preferential activation of some signaling pathways over others. The mu opioid receptor primarily signals through G proteins (Gi/o) and β-arrestin. G protein activation leads to analgesia (pain relief), while β-arrestin recruitment is associated with adverse effects such as respiratory depression and constipation. A biased agonist is a drug that, upon binding to the mu receptor, preferentially activates the G protein pathway while minimizing β-arrestin recruitment. This means it can provide effective pain relief with a reduced risk of respiratory depression and constipation. For example, oliceridine is a biased agonist at the mu opioid receptor designed to favor G protein signaling over β-arrestin signaling. By selectively targeting beneficial pathways and avoiding those that cause harm, biased agonism offers the potential to develop safer and more effective opioid analgesics.