Differential antagonism of the rate-decreasing effects of kappa-opioid receptor agonists by naltrexone and norbinaltrophimine

Eight K-opioid receptor agonists were examined for their effects in squirre l monkeys responding under a fixed interval 5-min schedule of stimulus term ination. Six of these K-opioid receptor agonists decreased dose-dependently the total number of responses and with an order of potency consistent with K-opioid receptor interaction. Three of these K-opioid receptor agonists, bremazocine, U69,593 {[(5a,7a,8b)-(+)-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5) dec-8-yl)] benzeneacetamide} and enadoline, were evaluated following pretre atment with 1.0 mg/kg of naltrexone or 3.0 mg/kg of norbinaltorphimine. The effects of the three agonists were antagonized significantly by naltrexone , but only those of bremazocine and U69,593 were antagonized significantly by norbinaltorphimine. Statistical analysis of the data averaged over six m onkeys revealed that naltrexone was significantly more potent than norbinal torphimine at antagonizing enadoline and U69,593, but naltrexone and norbin altorphimine were equipotent at antagonizing bremazocine. Moreover, naltrex one was 8-fold more potent at antagonizing U69,593 and enadoline than at an tagonizing bremazocine. These results suggest that under these conditions t he effects of U69,593 and enadoline may be mediated, in part, by a differen t receptor population, perhaps a subtype of kappa-opioid receptors, from th e one that mediates the effects of bremazocine. (C) 1999 Elsevier Science B .V. All rights reserved.