Possible biased analgesic of hydromorphone through the G protein-over ß-arrestin-mediated pathway: cAMP, CellKey™, and receptor internalization analyses.
J Pharmacol Sci
; 140(2): 171-177, 2019 Jun.
Article
em En
| MEDLINE
| ID: mdl-31320243
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 ß-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 ß-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 ß-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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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AMP Cíclico
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Receptores Opioides mu
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Proteínas de Ligação ao GTP
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Hidromorfona
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Beta-Arrestinas
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Analgésicos Opioides
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article