The NMDA antagonist MK-801 induces hyperalgesia and increases CSF excitatory amino acids in rats: reversal by guanosine.
Excitatory amino acids (EAAs) and their receptors play a central role in the mechanisms underlying pain transmission. NMDA-receptor antagonists such as MK-801 produce antinociceptive effects against experimental models of chronic pain, but results in acute pain models are conflicting, perhaps due to increased glutamate availability induced by the NMDA-receptor antagonists. Since guanosine and riluzole have recently been shown to stimulate glutamate uptake, the aim of this study was to examine the effects of guanosine or riluzole on changes in nociceptive signaling induced by MK-801 in an acute pain model. Rats received an i.p. injection of vehicle, morphine, guanosine, riluzole or MK-801 or a combined treatment (vehicle, morphine, guanosine or riluzole+MK-801) and were evaluated in the tail flick test, or had a CSF sample drawn after 30 min. Riluzole, guanosine, and MK-801 (0.01 or 0.1 mg/kg) did not affect basal nociceptive responses or CSF EAAs levels. However, MK-801 (0.5 mg/kg) induced hyperalgesia and increased the CSF EAAs levels; both effects were prevented by guanosine, riluzole or morphine. Hyperalgesia was correlated with CSF aspartate and glutamate levels. This study provides additional evidence for the mechanism of action of MK-801, showing that MK-801 induces hyperalgesia with parallel increase in CSF EAAs levels.
Schmidt
André P
AP
Department of Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil. aschmidt@ufrgs.br
Tort
Adriano B L
AB
Silveira
Patrícia P
PP
Böhmer
Ana Elisa
AE
Hansel
Gisele
G
Knorr
Luisa
L
Schallenberger
Cristhine
C
Dalmaz
Carla
C
Elisabetsky
Elaine
E
Crestana
Rosa H
RH
Lara
Diogo R
DR
Souza
Diogo O
DO
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018846:Excitatory Amino Acids / Q000134:cerebrospinal fluid*; D006151:Guanosine / Q000494:pharmacology*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000523:psychology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D019782:Riluzole / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; D006151:Guanosine; D016291:Dizocilpine Maleate; D009020:Morphine; D019782:Riluzole