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*

*Corresponding author for this work

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

60 Citations (Scopus)
342 Downloads (Pure)

Abstract

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 (Gi) 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 Gi 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
Volume175
Issue number13
Early online date14 May 2018
DOIs
Publication statusPublished - 15 Jul 2018

Keywords

  • Journal Article

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