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

Research output: Contribution to journalArticle

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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 (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
Volume175
Issue number13
Early online date26 Mar 2018
DOIs
Publication statusPublished - 1 Jul 2018

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mu Opioid Receptor
Respiration
Morphine
Arrestin
Tidal Volume
GTP-Binding Proteins
Opioid Analgesics
Whole Body Plethysmography
Ligands
Enkephalins
HEK293 Cells
Respiratory Rate
Respiratory Insufficiency
beta-Arrestin 2

ASJC Scopus subject areas

  • Pharmacology

Cite this

The novel μ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception. / Hill, Rob; Disney, Alex; Conibear, Alex; Sutcliffe, Katy; Dewey, William; Husbands, Stephen; Bailey, Chris; Kelly, Eamonn; Henderson, Graeme.

In: British Journal of Pharmacology, Vol. 175, No. 13, 01.07.2018, p. 2653-2661.

Research output: Contribution to journalArticle

Hill, Rob ; Disney, Alex ; Conibear, Alex ; Sutcliffe, Katy ; Dewey, William ; Husbands, Stephen ; Bailey, Chris ; Kelly, Eamonn ; Henderson, Graeme. / The novel μ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception. In: British Journal of Pharmacology. 2018 ; Vol. 175, No. 13. pp. 2653-2661.
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AU - Dewey, William

AU - Husbands, Stephen

AU - Bailey, Chris

AU - Kelly, Eamonn

AU - Henderson, Graeme

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