The novel μ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception

Rob Hill, Alex Disney, Alex Conibear, Katy Sutcliffe, William Dewey, Stephen Husbands, Chris Bailey, Eamonn Kelly, Graeme Henderson

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Background and Purpose: PZM21 is a novel μ-opioid receptor ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic of classical μ receptor ligands such as morphine. We have re-examined the signalling profile of PZM21 and its ability to depress respiration. Experimental Approach: G protein (G i) activation and arrestin-3 translocation were measured in vitro, using BRET assays, in HEK 293 cells expressing μ receptors. Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole-body plethysmography, and antinociception was measured by the hot plate test. Key Results: PZM21 (10 −9 – 3 × 10 −5 M) produced concentration-dependent G i activation and arrestin-3 translocation. Comparison with responses evoked by morphine and DAMGO revealed that PZM21 was a low efficacy agonist in both signalling assays. PZM21 (10–80 mg·kg −1) depressed respiration in a dose-dependent manner. The respiratory depression was due to a decrease in the rate of breathing not a decrease in tidal volume. On repeated daily administration of PZM21 (twice daily doses of 40 mg·kg −1), complete tolerance developed to the antinociceptive effect of PZM21 over 3 days but no tolerance developed to its respiratory depressant effect. Conclusion and Implications: These data demonstrate that PZM21 is a low efficacy μ receptor agonist for both G protein and arrestin signalling. Contrary to a previous report, PZM21 depresses respiration in a manner similar to morphine, the classical opioid receptor agonist.

Original languageEnglish
Pages (from-to)2653-2661
Number of pages9
JournalBritish Journal of Pharmacology
Issue number13
Early online date26 Mar 2018
Publication statusPublished - 1 Jul 2018

Bibliographical note

© 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

ASJC Scopus subject areas

  • Pharmacology


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