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

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  • Effect of NMDA receptor antagonists on

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In a previous study we indicated the involvement of the N-methyl-D-aspartate (NMDA) receptor in the development of morphine dependence as assessed by naloxone-induced rise in norepinephrine release in chronically morphine-treated rats. In the present experiments, we studied (1) the possible role of protein kinases in the increased norepinephrine release occurring after naloxone injection and (2) the effects of NMDA receptor antagonists on chronic morphine exposure-induced changes in protein kinase activity. The naloxone-induced rise in norepinephrine release was attenuated by concomitant administration of a protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H-7) or an NMDA receptor antagonist, (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a, d]-cyclohepten-5, 10-imine hydrogen maleate (dizocilpine, MK-801) with morphine. Both cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), which mediate neurotransmitter release, were clearly activated in the cytosol of the pons/medulla, but not in that of the hippocampus, in chronically morphine-treated rats. This activation of PKA and PKC by chronic morphine treatment was inhibited by infusion of dizocilpine or D(-)-2-amino-5-phosphonopentanoic acid (AP-5), an ionotropic glutamate receptor antagonist, together with morphine. These results suggest that NMDA receptor antagonists inhibit the increase in protein kinase activity produced by chronic morphine treatment, thus suppressing the naloxone-induced rise in norepinephrine release.

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