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

• Published in: Journal of pharmacological sciences 2019-06, Vol.140 (2), p.171-177
• Main Authors: Manabe, Sei, Miyano, Kanako, Fujii, Yuriko, Ohshima, Kaori, Yoshida, Yuki, Nonaka, Miki, Uzu, Miaki, Matsuoka, Yoshikazu, Sato, Tetsufumi, Uezono, Yasuhito, Morimatsu, Hiroshi
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - adverse effects; Analgesics, Opioid - pharmacology; beta-Arrestins - metabolism; Biased agonist; Cyclic AMP; G protein; GTP-Binding Proteins - metabolism; HEK293 Cells; Humans; Hydromorphone; Hydromorphone - adverse effects; Hydromorphone - metabolism; Hydromorphone - pharmacology; Receptors, Opioid, mu - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; β-arrestin; μ-opioid receptor
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2019.06.005

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™ cAMP, CellKey™, and receptor internalization assays were performed with four different types of cells stably expressing differentially labelled MOR. EC50 values measured by cAMP and CellKey™ assays had potencies in the order fentanyl ≤ hydromorphone