Effect of NMDA receptor antagonists on protein kinase activated by chronic morphine treatment

• Published in: Japanese Journal of Pharmacology Vol. 73; no. suppl.1; p. 141
• Main Authors: Iwai, Miho, Makimura, Mizue, Fukuda, Hideeomi
• Format: Journal Article
• Language: English; Japanese
• Published: The Japanese Pharmacological Society 1997
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1016/S0021-5198(19)45064-6

In chronically morphine-treated rats, the level of norepinephrine (NE) in the hippocampus increased after naloxone challenge and the rise in NE release was long-lasting for at least 2 hr. We found that dizocilpine (MK-801) infusion (intracerebroventricle, i.c.v.) together with morphine for 72 hr decreased the sustained rise in hippocampal NE release after naloxone injection (s.c.). In order to clarify the mechanism underlying the sustained rise in NE release and the inhibitory effect of dizocilpine on hippocampal NE release, we examined the activity of protein kinases which mediated the release of neurotransmitters. Both cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) in the pons/medulla were activated by chronic administration of morphine. The enhancement of cytosolic PKA and PKC activity in the pons/medulla produced by chronic morphine treatment was blocked by the combination with naloxone. Concurrent administration of dizocilpine or AP-5, an ionotropic glutamate receptor antagonist, with morphine inhibited not only activation of PKC but also that of PKA. These results may provide evidence for the involvement of the NMDA receptor in the expression of morphine dependence.