The effect of the irreversible mu-opioid receptor antagonist clocinnamox on morphine potency, receptor binding and receptor mRNA.
Academic Article
Overview
abstract
In these experiments, the effect of the irreversible mu-opioid receptor antagonist clocinnamox on the potency of morphine, opioid receptor binding and mu-opioid receptor mRNA was examined. Mice were injected with clocinnamox (0.32-12.8 mg/kg) and the analgesic potency of morphine was examined 24 h later. Clocinnamox produced a dose-dependent decrease in the potency of morphine; and at the higher dose of clocinnamox the maximal analgesic effect was not observed following doses of morphine in excess of 500 mg/kg s.c. In saturation binding studies in brain, clocinnamox (0.32-25.6 mg/kg) dose-dependently decreased mu-opioid ([3H][D-Ala2,MePhe4,Gly-ol5]enkephalin; DAMGO) receptor Bmax with relatively minimal effects on Kd. Binding to delta-opioid receptor ([3H][D-Pen2,D-Pen5]enkephalin; DPDPE) and kappa-opioid receptor ([3H](5,7,8)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec -8-yl) benzeneacetamide; U69,593) was not affected by clocinnamox. The effect of clocinnamox was time-dependent in that the greatest changes in morphine potency and mu-opioid receptor density were observed within 24 h of administration and decreased with time (336 h). Although mu-opioid receptor density was decreased to less than 30% of control 24 h following clocinnamox (12.8 mg/kg) and had increased to 80% by 5 days, a solution hybridization assay for mu-opioid receptor mRNA transcript revealed no changes in the steady-state levels of this mRNA. These studies indicate that clocinnamox is an irreversible antagonist at the mu-opioid receptor since it appears to selectively affect receptor density with minimal effects on affinity. Furthermore, clocinnamox produces time- and dose-dependent changes in Bmax and these changes appear to be unrelated to changes in mu-opioid receptor mRNA. It is possible that the repopulation of brain by mu-opioid receptors following clocinnamox is mediated by an existing pool of receptors that are activated following treatment.
