The aim of the present investigation was to determine if chronic activ
ation of kappa-opioid receptor induces development of tolerance and de
pendence to kappa-opioid agonists on the isolated right atrium of the
rat. Tolerance to the kappa-agonist was induced by chronic administrat
ion of U-50,488H, a selective kappa-agonist (15 mg/kg i.p. twice a day
for 4 days), The rats were killed on day 5. Tolerance to U-50,488H wa
s observed after its chronic administration and was revealed as a righ
tward shift of the concentration-response curve; it was accompanied by
a decrease in the maximum response and in the slope, Withdrawal to th
e kappa-agonist was induced by administration of Mr-2266 (preferential
ly kappa-antagonist) or nor-binaltorphimine (nor-bni; selective kappa-
antagonist) to the organ bath. The administration of the kappa-antagon
ists Mr-2266 or nor-bni to preparations from tolerant rats in the orga
n bath induced an increase in auricular contraction frequency, In cont
rast, the administration of the kappa-antagonists to preparations from
vehicle-treated rats induced a decrease in auricular contraction freq
uency. These findings demonstrate that the hearts of rats that had rec
eived chronic U-50488H treatment develop tolerance to the cardiac effe
cts of U-50,488H and exhibit excitatory reactions to kappa-antagonist'
s precipitated withdrawal.