Carfentanil is a β-arrestin-biased agonist at the μ opioid receptor

Nokomis Ramos-Gonzalez, Sam Groom, Katy J Sutcliffe, Sukhvinder Bancroft, Chris P Bailey, Richard B Sessions, Graeme Henderson, Eamonn Kelly

Research output: Contribution to journalArticlepeer-review

4 Citations (SciVal)

Abstract

BACKGROUND AND PURPOSE: The illicit use of fentanyl-like drugs (fentanyls), which are μ opioid receptor agonists, and the many overdose deaths that result, has become a major problem. Fentanyls are very potent in vivo, leading to respiratory depression and death. However, the efficacy and possible signalling bias of different fentanyls is not clearly known. Here, we compared the relative efficacy and bias of a series of fentanyls.

EXPERIMENTAL APPROACH: For agonist signalling bias and efficacy measurements, Bioluminescence Resonance Energy Transfer experiments were undertaken in HEK293T cells transiently transfected with μ opioid receptors, to assess Gi protein activation and β-arrestin 2 recruitment. Agonist-induced cell surface receptor loss was assessed using an enzyme-linked immunosorbent assay, whilst agonist-induced G protein-coupled inwardly rectifying potassium channel current activation was measured electrophysiologically from rat locus coeruleus slices. Ligand poses in the μ opioid receptor were determined in silico using molecular dynamics simulations.

KEY RESULTS: Relative to the reference ligand DAMGO, carfentanil was β-arrestin-biased, whereas fentanyl, sufentanil and alfentanil did not display bias. Carfentanil induced potent and extensive cell surface receptor loss, whilst the marked desensitisation of G protein-coupled inwardly rectifying potassium channel currents in the continued presence of carfentanil in neurones was prevented by a GRK2/3 inhibitor. Molecular dynamics simulations suggested unique interactions of carfentanil with the orthosteric site of the receptor that could underlie the bias.

CONCLUSIONS AND IMPLICATIONS: Carfentanil is a β-arrestin-biased opioid drug at the μ receptor. It is uncertain how such bias influences in vivo effects of carfentanil relative to other fentanyls.

Original languageEnglish
Pages (from-to)2341-2360
Number of pages20
JournalBritish Journal of Pharmacology
Volume180
Issue number18
Early online date2 Apr 2023
DOIs
Publication statusPublished - 30 Sept 2023

Bibliographical note

Funding Information:
This work was supported by grants from the Biotechnology and Biological Sciences Research Council (DTP2: BB/M009122/1) to N.R.G., R.B.S. and E.K., and from the Medical Research Council (MR/S010890/1) to G.H. and E.K.

Keywords

  • G protein
  • bias
  • carfentanil
  • fentanyl
  • β-arrestin

ASJC Scopus subject areas

  • Pharmacology

Fingerprint

Dive into the research topics of 'Carfentanil is a β-arrestin-biased agonist at the μ opioid receptor'. Together they form a unique fingerprint.

Cite this