Paradoxical convulsant action of a novel non-competitive N-methyl-D-aspartate (NMDA) antagonist, tiletamine.

Abstract

Intracerebroventricular (i.c.v.) injection of tiletamine, 0.001 mumol, a presumed non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, protected mice from convulsions induced by NMDA and quinolinate, but not from those induced by excitatory amino acids interacting preferentially with non-NMDA receptors. At higher doses, however, tiletamine induced convulsions by itself. Tiletamine-induced convulsions were antagonized by the broad spectrum excitatory amino acid antagonist, gamma-D-glutamylamino-methylsulphonate (gamma-D-GAMS), and were potentiated by the competitive NMDA antagonist, 2-amino-7-phosphonohepatanoate (AP7). Intrathecal (i.t.) injection of tiletamine, 0.01-1.0 mumol, dose-dependently suppressed spinal flexor reflexes. Tiletamine, 0.01 and 0.1 mumol, failed to affect spinal Hoffman- (H-) reflexes, whereas tiletamine, 1.0 mumol, led to a 50% increase of the H-reflex amplitude. It is concluded that the anticonvulsant and reflex suppressant action of tiletamine are due to antagonism of NMDA receptor-mediated excitation. The convulsant effect of tiletamine and its excitatory effect on spinal H-reflexes at higher doses, however, appear to be mediated by non-NMDA receptors.

• Authors: T Klockgether, L Turski, M Schwarz, K H Sontag, J Lehmann
• Journal: Brain research (Brain Res) Vol. 461 Issue 2 Pg. 343-8 (Oct 04 1988) ISSN: 0006-8993 [Print] Netherlands
• PMID: 2846121 (Publication Type: Journal Article)

Chemical References

• Anticonvulsants
• Cyclohexanes
• Quinolinic Acids
• Receptors, N-Methyl-D-Aspartate
• Receptors, Neurotransmitter
• Tiletamine
• Aspartic Acid
• N-Methylaspartate
• Quinolinic Acid

Topics

• Animals
• Anticonvulsants (pharmacology)
• Aspartic Acid (analogs & derivatives, pharmacology)
• Cyclohexanes (pharmacology)
• Dose-Response Relationship, Drug
• Injections, Intraventricular
• Male
• Mice
• N-Methylaspartate
• Quinolinic Acid
• Quinolinic Acids (pharmacology)
• Receptors, N-Methyl-D-Aspartate
• Receptors, Neurotransmitter (drug effects, physiology)
• Reflex, Monosynaptic (drug effects)
• Seizures (chemically induced)
• Tiletamine (pharmacology)