Abstract
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.
Highlights
Opioid-induced respiratory depression is the primary cause of death following illicit or prescription opioid misuse
The idea that a G protein-biased μ receptor agonist would have a reduced ‘on target’ side effect profile arises from the observation that in arrestin-3 (β-arrestin 2) knockout mice, morphine, the prototypical opioid agonist, showed a reduced propensity to produce respiratory depression and constipation (Raehal et al, 2005) implying that respiratory depression resulted from μ receptor coupling to arrestinmediated signalling
We compared the responses evoked by PZM21 to those evoked by two well-characterized μ receptor ligands, DAMGO and morphine in the same assay
Summary
Opioid-induced respiratory depression is the primary cause of death following illicit or prescription opioid misuse. Current therapeutically useful opioid ligands such as morphine produce their analgesic and respiratory depressant effects through activation of the μ-opioid receptor (μ receptor) (Matthes et al, 1996). The idea that a G protein-biased μ receptor agonist would have a reduced ‘on target’ side effect profile arises from the observation that in arrestin-3 (β-arrestin 2) knockout mice, morphine, the prototypical opioid agonist, showed a reduced propensity to produce respiratory depression and constipation (Raehal et al, 2005) implying that respiratory depression resulted from μ receptor coupling to arrestinmediated signalling. 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. 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
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