ENHANCEMENT OF THE RATE OF GTP HYDROLYSIS IN RAT-BRAIN BY REPEATED KAPPA-OPIOID TREATMENT

To investigate the G protein and protein kinase C (PKC) systems during the initial state of kappa-opioid tolerance, the low K-m GTPase and P KC activities were measured following repeated treatment of rat with t he kappa-agonist, U-50,488. In behavioral studies, antinociceptive tol erance to U-50,488 was developed following 7-day treatment with U-50,4 88. Under these conditions, repeated administration of U-50,488 signif icantly enhanced the basal low K-m GTPase activity in the pons/medulla but not in the cortex and midbrain regions. On the other hand, repeat ed U-50,488 treatment had no effect on PKC activity in cytosol and mem brane fractions under the calcium-chelating conditions. These results indicate that repeated administration of kappa-agonist, U-50,488, incr eases in the basal hydrolysis of GTP to GDP in rat pons/medulla but no t PKC activity which was observed in the case of repeated administrati on with morphine in rats.