ANTINOCICEPTIVE AND RESPONSE RATE-ALTERING EFFECTS OF KAPPA-OPIOID AGONISTS, SPIRADOLINE, ENADOLINE AND U69,593, ALONE AND IN COMBINATION WITH OPIOID ANTAGONISTS IN SQUIRREL-MONKEYS

Effects of the kappa opioid agonists, spiradoline (U62,066), enadoline (Cl-977) and U69,593, were examined alone and in combination with the opioid antagonists quadazocine and beta-funaltrexamine in squirrel mo nkeys that responded under a schedule of shock titration. When given a lone, each of these agonists increased the intensity at which the monk eys maintained shock 50% of the time (median shock level, MSL). Lower doses of spiradoline, enadoline and U69,593 increased response rates i n some monkeys and higher doses decreased response rates in all monkey s. When given in combination with the opioid antagonist quadazocine, t he dose-effect curves of each agonist, both for MSL and response rates , were shifted to the right in a dose-related and parallel manner. The slopes for the regression lines of the Schild plots for each agonist- quadazocine interaction approximated unity and apparent pA(2) values f or quadazocine in combination with these agonists ranged between 6.68 and 6.81 for MSL and between 6.63 and 6.87 for response rate. The effe cts of these agonists were not changed by an 8.0 mg/kg dose of beta-fu naltrexamine that markedly antagonized the effects of morphine. These results parallel those previously obtained with other kappa agonists, such as bremazocine and U50,488 and suggest that the antinociceptive e ffects of spiradoline, enadoline and U69,593 in the shock-titration pr ocedure in squirrel monkeys relate to activity at non-mu, probably kap pa, opioid receptors.