RESUMO
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.