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

Research output: Contribution to journalArticle (Academic Journal)peer-review

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BACKGROUND AND PURPOSE: The illicit use of fentanyl-like drugs (fentanyls), which are μ opioid receptor agonists, and the number of 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 efficacies 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 receptor, 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 by electrophysiological recording 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.

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

Original languageEnglish
Pages (from-to)2341-2360
Number of pages20
JournalBritish Journal of Pharmacology
Issue number18
Early online date2 Apr 2023
Publication statusE-pub ahead of print - 2 Apr 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.

Publisher Copyright:
© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.


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