Non-competitive N-methyl-D-aspartic Acid Research Articles

Differential antagonism by MK-801 against antinociception induced by opioid receptor agonists administered supraspinally in mice

Various doses of MK-801 ((±)-5-methyl-10,11-dihydro-5 H-dibezo ( a, d)cylohepten-5,10-imine maleate), a non-competitive N- methyl- D-aspartic acid (NMDA) receptor antagonist (0.001–1 μg) injected intracerebroventricularly (i.c.v.) alone did not show any antinociceptive effect. MK-801 (0.001–1 μg i.c.v.) dose dependently attenuated the inhibition of the tail-flick and hot plate responses induced by i.c.v. administered morphine (1 μg), [ D-Pen 2, D-Pen 5]enkephalin (DPDPE; 10 μg), and U50,488H ( trans-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)cyclohexyl]benzeocetamide; 60 μg). However, the inhibition of the tail-flick and hot plate responses induced by i.c.v. administered β-endorphin (1 μg) was not changed by i.c.v. administered MK-801. Our results indicate that, at the supraspinal level, NMDA receptors are involved in the production of antinociception induced by supraspinally administered morphine, DPDPE, and U50,488H but not β-endorphin.

Antagonism of various tonic convulsions in mice by dextrorphan and dizocilpine

To define their efficacy and mechanism of action, the possible antagonistic effects of intravenously administered dextrorphan and dizocilpine, non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonists, on tonic convulsions and death in a variety of experimental mice models were compared. Dextrorphan not only produced dose-dependent protection against the tonic convulsions caused by an intracerebroventricular injection of NMDA, but also showed a broad spectrum of anticonvulsant activities against tonic convulsions caused by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA), bicuculline, pentylenetetrazole or electroconvulsive shock. The anticonvulsant action of dizocilpine was found to be more efficacious for any type of tonic convulsions and was 20- to 70-fold more potent than that of dextrorphan. Dizocilpine, unlike dextrorphan, impaired motor function at doses showing its anticonvulsant activity. Bay k-8644 (a Ca2+ channel agonist)-induced seizures were not antagonized by dextrorphan. Dextrorphan and dizocilpine were characteristically selective for protective functions against death, especially with three subtypes of glutamate receptors, as death caused by NMDA but not by AMPA and KA was selectively and markedly inhibited by both dextrorphan and dizocilpine. In view of these results, the efficacy of dextrorphan and dizocilpine as antagonists of convulsant effects appears to be consistent with the interpretation that a variety of convulsants cause tonic convulsions via direct or indirect interaction with the NMDA receptor complex. Furthermore, it is suggested that influx of Ca(2+) and intracellular Ca(2+) activity, such as the Bay k-8644-modulated activation of Ca(2+) binding proteins, are not directly modified by the administration of dextrorphan, itself.

Identification of a novel NMDA receptor in rat cerebellum

Specific binding sites for the noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist. [ 3H]MK-801, were identified in synaptic membranes isolated from rat cerebellum. The density of these sites (0.61 pmol/mg protein), derived from linear Scatchard plots, was lower than those measured in a number of forebrain regions (0.81–2.96 pmol/mg protein). The K d value for cerebellar [ 3H]MK-801 binding sites (37.7 nM) was markedly higher than those (1.53–1.82 nM) detected in rat forebrain regions. Experiments were carried out in the presence of 30 μM L-glutamic acid and 1 μM glycine, and after a 210 min incubation [ 3H]MK-801 binding was maximally stimulated. The pharmacology of these cerebellar [ 3H]MK-801 binding sites was markedly different from that of [ 3H]MK-801 sites in the rat cortex. These data have highlighted a novel population of NMDA receptors, which are functionally coupled to an ion channel but exhibit remarkedly weak affinity for MK-801.