Limitations and potential of κOR biased agonists for pain and itch management

The concept of ligand bias is based on the premise that different agonists can elicit distinct responses by selectively activating the same receptor. These responses often determine whether an agonist has therapeutic or undesirable effects. Therefore, it would be highly advantageous to have agonists that specifically trigger the therapeutic response. The last two decades have seen a growing trend towards the consideration of ligand bias in the development of ligands to target the κ-opioid receptor (κOR). Most of these ligands selectively favor G-protein signaling over β-arrestin signaling to potentially provide effective pain and itch relief without adverse side effects associated with κOR activation. Importantly, the specific role of β-arrestin 2 in mediating κOR agonist-induced side effects remains unknown, and similarly the therapeutic and side-effect profiles of G-protein-biased κOR agonists have not been established. Furthermore, some drugs previously labeled as G-protein-biased may not exhibit true bias but may instead be either low-intrinsic-efficacy or partial agonists. In this review, we discuss the established methods to test ligand bias, their limitations in measuring bias factors for κOR agonists, as well as recommend the consideration of other systematic factors to correlate the degree of bias signaling and pharmacological effects.