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The novel μ‐opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception
Author(s) -
Hill Rob,
Disney Alex,
Conibear Alex,
Sutcliffe Katy,
Dewey William,
Husbands Stephen,
Bailey Chris,
Kelly Eamonn,
Henderson Graeme
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14224
Subject(s) - damgo , agonist , μ opioid receptor , pharmacology , receptor , chemistry , opioid , respiration , morphine , respiratory rate , arrestin , intrinsic activity , endocrinology , medicine , opioid receptor , g protein coupled receptor , heart rate , biochemistry , anatomy , blood pressure
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.