In Vivo Efficacy of 3 Opioid Analgesics in the Mouse.

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It has been suggested that opioid agonist efficacy is a determinant of μ-opioid receptor (μOR) density regulation. In this study, the irreversible μOR antagonist Clocinnamox (CCAM) was used to alkylate receptors in the intact mouse to examine the in vivo efficacy of 3 opioid analgesics. CCAM has been shown to dose-dependently reduce μOR density in the mouse CNS and can be employed to estimate agonist efficacy using receptor depletion. Initially, the time of peak effect (15min) and the ED50 (0.6ug/kg, 16.6mg/kg, 1.0mg/kg; etorphine, propoxyphene, oxycodone) was estimated using the tailflick assay. To reduce animal use, efficacy studies were conducted using a cumulative dose-response protocol which yields ED50s similar to those determined using a standard dosing protocol. Mice were injected ip with saline or CCAM (0.32–12.8mg/kg) and 24hr later, cumulative dose-response studies were conducted with each agonist. CCAM dose-dependently increased the ED50 for each agonist. The mean rightward shift in the ED50 following 12.8mg/kg of CCAM was 5-fold for etorphine and propoxyphene, and 12-fold for oxycodone. Initial analysis using the operational model of agonism indicated that CCAM dose-dependently reduced μOR by 25–80% and that the relative efficacy ranking was etorphine propoxyphene > oxycodone. These results suggest that oxycodone is a relatively low intrinsic efficacy agonist. Previous studies have shown that chronic etorphine, but not oxycodone, reduces μOR density. Taken together, these data are consistent with suggestions that chronic treatment with a low intrinsic efficacy μ-opioid agonist does not downregulate μOR density.