A PROTEIN-KINASE INHIBITOR, H-7, INHIBITS THE DEVELOPMENT OF TOLERANCE TO OPIOID ANTINOCICEPTION

To investigate the effect of a protein kinase inhibitor, 1-(5-isoquino linesulfonyl)-2-methylpiperazine (H-7), on the development of toleranc e to antinociception induced by morphine (mu-opioid receptor agonist) and butorphanol (mu/delta/kappa-mixed opioid receptor agonist), rats w ere infused i.c.v. with morphine, butorphanol and H-7 through osmotic minipumps for 3 days. Concomitant infusion of H-7 dose dependently inh ibited the development of tolerance to i.c.v. morphine- and butorphano l-induced antinociception. These results suggest that protein kinases may play an important role in the development of opioid tolerance.