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

Sei Manabe, Kanako Miyano, Yuriko Fujii, Kaori Ohshima, Yuki Yoshida, Miki Nonaka, Miaki Uzu, Yoshikazu Matsuoka, Tetsufumi Sato, Yasuhito Uezono, Hiroshi Morimatsu

Research output: Contribution to journalArticle

2 Citations (Scopus)

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™ 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 < morphine ≤ oxycodone, all also exhibiting full agonist responses. However, in the internalization assay, only fentanyl elicited a full agonist response. Hydromorphone had the strongest potency next to fentanyl; however, contribution of the β-arrestin-mediated pathway was small, suggesting that its effect could be biased toward the G protein-mediated pathway. Based on these properties, hydromorphone could be chosen as an effective analgesic.

Original languageEnglish
Pages (from-to)171-177
Number of pages7
JournalJournal of Pharmacological Sciences
Volume140
Issue number2
DOIs
Publication statusPublished - Jun 2019

Keywords

  • Biased agonist
  • G protein
  • Hydromorphone
  • β-arrestin
  • μ-opioid receptor

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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