• Rob Hill, Alex Disney, Alex Conibear, Katy Sutcliffe, William Dewey, Stephen Husbands, Chris Bailey, Eamonn Kelly, and Graeme Henderson.
• School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.
• Br. J. Pharmacol. 2018 Jul 1; 175 (13): 2653-2661.

Background And PurposePZM21 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 ApproachG 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 ResultsPZM21 (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 ImplicationsThese 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.© 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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