OPIOIDS AND RATE OF POSITIVELY REINFORCED BEHAVIOR .3. ANTAGONISM BY THE LONG-LASTING KAPPA-ANTAGONIST NORBINALTORPHIMINE

Various opioid compounds were examined before and after administration of a 40 mu g (i.c.v.) dose of norbinaltorphimine (nor-BNI) in rats re sponding under a fixed ratio 20 schedule of food presentation, At time points ranging from 1 to 133 days after administration of nor-BNI, th e dose-effect curve for the kappa opioid bremazocine was shifted to th e right of that obtained prior to the administration of nor-BNI. The m agnitude of these rightward shifts were somewhat larger at day 14 than day 1, remained unchanged between days 14 and 39, and then declined b etween days 70 and 133, Nor-BNI also produced large rightward shifts i n the dose-effect curves for the kappa opioids U50,488, spiradoline an d U69,593, and a small rightward shift in the curve for ethylketocycla zocine. Tn contrast, nor-BNI did not alter the dose-effect curves for (-)n-allylnormetazocine, (-)-cyclazocine, nalorphine and the mu opioid morphine. The present findings indicate that the rate-decreasing effe cts of bremazocine, U50,488, U69,593, spiradoline and ethylketocyclazo cine are mediated by agonist activity at the kappa opioid receptor(s). These findings also indicate that nor-BNI is a long-lasting and kappa opioid-selective antagonist that offers a number of advantages over n aloxone and naltrexone as a pharmacological tool for examining the kap pa opioid-mediated activity of opioid compounds.