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-isoquinolinesulfonyl)-2-methylpiperazine (H-7), on the development of tolerance to antinociception induced by morphine (μ-opioid receptor agonist) and butorphanol (μ/δ/κ-mixed opioid receptor agonist), rats were infused i.c.v. with morphine, butorphanol and H-7 through osmotic minipumps for 3 days. Concomitant infusion of H-7 dose dependently inhibited the development of tolerance to i.c.v. morphine- and butorphanol-induced anticiception. These result suggest that protein kinases may play an important role in the development of opioid tolerance.