Paradoxical convulsant action of a novel non-competitive N-methyl-D-aspartate (NMDA) antagonist, tiletamine.
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.
Klockgether
T
T
Max Planck Institute for Experimental Medicine, Göttingen, F.R.G.
Turski
L
L
Schwarz
M
M
Sontag
K H
KH
Lehmann
J
J
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D016202:N-Methylaspartate; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*; D012023:Reflex, Monosynaptic / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced*; D013992:Tiletamine / Q000494:pharmacology*
D000927:Anticonvulsants; D003510:Cyclohexanes; D011805:Quinolinic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D013992:Tiletamine; D001224:Aspartic Acid; D016202:N-Methylaspartate; D017378:Quinolinic Acid