Opioid Agonist Effects on Mouse Writhing After Irreversible Mu Receptor Blockade With Clocinnamox

The antinociceptive effects of the mu opioid agonists morphine, fentanyl, etonitazene, and the high-potency fentanyl analog NIH 10741 were assessed before and after administration of the irreversible mu opioid antagonist clocinnamox (CCAM) in a mouse acetic acid-induced writhing procedure. CCAM caused hyperalgesia and shifted the dose-response curves of all 4 tested agonists to the right in a dose-dependent manner without, however, preventing the complete suppression of writhes by agonist doses > 100-10,000 times their respective ED₅₀ values. In the case of etonitazene and NIH 10741, 10 mg/kg CCAM produced biphasic agonist dose-response curves. Further experiments with naltrexone, naltrindole, and nor-binaltorphimine suggested that in the presence of 10 mg/kg CCAM, low-to intermediate-agonist doses produced mu opioid-mediated antinociception, whereas very high agonist doses (530-2,800-fold higher than their ED₅₀ value under control conditions) suppressed writhing by nonopioid mechanisms.