Possible biased analgesic of hydromorphone through the G protein-over β-arrestin-mediated pathway: cAMP, CellKeyTM, and receptor internalization analyses

Abstract Morphine, fentanyl, and oxycodone are widely used as analgesics, and recently hydromorphone has been approved in Japan. Although all of these are selective for μ-opioid receptors (MORs) and have similar structures, their analgesic potencies and adverse effects (AEs) are diverse. Recent molecular analyses of MOR signaling revealed that the G protein-mediated signaling pathway causes analgesic effects and the β-arrestin-mediated signaling pathway is responsible for AEs. We used several cell-based analyses that selectively measure cellular responses activated by either G protein- or β-arrestin-mediated pathways. GloSensor TM cAMP, CellKey TM , and receptor internalization assays were performed with four different types of cells stably expressing differentially labelled MOR. EC 50 values measured by cAMP and CellKey TM assays had potencies in the order fentanyl≤hydromorphone