EXAMINATION OF THE KAPPA-AGONIST AND ANTAGONIST PROPERTIES OF OPIOIDSIN THE RAT DRUG DISCRIMINATION PROCEDURE - INFLUENCE OF TRAINING DOSEAND INTRINSIC EFFICACY

In a two-choice drug discrimination procedure, rats were trained to di scriminate either 0.056 (low dose) or 0.17 (high dose) mg/kg of the ka ppa opioid bremazocine from saline. Substitution and antagonism tests were then conducted with a variety of opioids. The opioids U50,488, et hylketocyclazocine, spiradoline, enadoline, and U69,593 substituted co mpletely (greater than or equal to 80% bremazocine-appropriate respond ing) for the bremazocine stimulus in both training groups, a finding c onsistent with their high-efficacy kappa profile. In contrast, the oth er opioids examined could be classified into different subsets on the basis of their patterns of substitution and antagonism: (1) (-)-cyclaz ocine substituted completely for the low-dose bremazocine stimulus and substituted partially (approximately 50% bremazocine-appropriate resp onding) for, and antagonized partially, the high-dose bremazocine stim ulus; (2) butorphanol, nalorphine and nalbuphine substituted partially for, and antagonized partially, the low- and high-dose bremazocine st imuli; (3) levallorphan did not substitute for either training dose of bremazocine and antagonized the bremazocine stimulus at both training doses; (4) (-)-N-allylnormetazocine [(-)-NANM] substituted partially for the low-dose bremazocine stimulus and substituted completely for t he high-dose bremazocine stimulus. Despite the high levels of substitu tion, (-)-NANM antagonized both the low- and high-dose bremazocine sti muli at doses below those required to produce its maximal agonist effe cts. The substitution patterns exhibited by (-)-NANM were not antagoni zed by doses of naloxone that antagonized the stimulus effects of (-)- cyctazocine and bremazocine, suggesting that these substitution patter ns were non-opioid mediated. Collectively, these results suggest that the different patterns of substitution and antagonism observed with th ese opioids were due either to differences in their intrinsic efficacy at the kappa receptor or to a non-opioid component of action.