The novel mu-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception

BACKGROUND AND PURPOSE PZM21 is a novel -opioid receptor ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic of classical 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 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 x 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 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.