Eight kappa-opioid receptor agonists were examined for their effects in squirrel monkeys responding under a fixed interval 3-min schedule of stimulus termination. Six of these kappa-opioid receptor agonists decreased dose-dependently the total number of responses and with an order of potency consistent with kappa-opioid receptor interaction. Three of these kappa-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 pretreatment 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 monkeys revealed that naltrexone was significantly more potent than norbinaltorphimine at antagonizing enadoline and U69,593, but naltrexone and norbinaltorphimine were equipotent at antagonizing bremazocine. Moreover, naltrexone was 8-fold more potent at antagonizing U69,593 and enadoline than at antagonizing bremazocine. These results suggest that under these conditions the effects of U69,593 and enadoline may be mediated, in part, by a different receptor population, perhaps a subtype of kappa-opioid receptors, from the one that mediates the effects of bremazocine.