Morphine-induced catalepsy is augmented by NMDA receptor antagonists, but is partially attenuated by an AMPA receptor antagonist

Glutamatergic transmission is an important factor in the development of neuronal death following transient cerebral ischemia. In this investigation the effects of N-methyl-d-aspartate (NMDA) and non-NMDA receptor antagonists on neuronal damage were studied in rats exposed to 10 min of transient cerebral ischemia induced by bilateral common carotid occlusion combined with hypotension. The animals were treated with a blocker of the ionotropic quisqualate or α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor, 2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo( F)quinoxaline (NBQX), given postischemia as an intraperitoneal bolus dose of 30 mg kg−1 followed by an intravenous infusion of 75 μg min−1 for 6 h, or with the noncompetitive NMDA receptor blocker dizocilpine(MK-801) given 1 mg kg−1 i.p. at recirculation and 3 h postischemia, or with the competitive NMDA receptor antagonist dl-( E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), 5 mg kg−1, given intraperitoneally at recirculation. Treatment with NBQX provided a significant reduction of neuronal damage in the hippocampal CA1 area by 44–69%, with the largest relative decrease in the temporal part of the hippocampus. In neocortex a significant decrease in the number of necrotic neurons was also noted. No protection could be seen following postischemic treatment with dizocilpine or CGP 40116. Our data demonstrate that AMPA but not NMDA receptor antagonists decrease neuronal damage following transient severe cerebral ischemia in the rat and that the protection by NBQX may be dependent on the severity of the ischemic insult. We propose that the AMPA receptor–mediated neurotoxicity could be due to ischemia-induced changes in the control mechanisms of AMPA receptor–coupled processes or to changes of AMPA receptor characteristics.

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Inhibition of kainic acid induced expression of interleukin-1β and interleukin-1 receptor antagonist mRNA in the rat brain by NMDA receptor antagonists

Molecular Brain Research ◽

10.1016/s0169-328x(00)00251-5 ◽

2000 ◽

Vol 85 (1-2) ◽

pp. 103-113 ◽

Cited By ~ 24

Author(s):

Charlotta Eriksson ◽

Li-Ping Zou ◽

Sven Ahlenius ◽

Bengt Winblad ◽

Marianne Schultzberg

Keyword(s):

Nmda Receptor ◽

Receptor Antagonist ◽

Rat Brain ◽

Kainic Acid ◽

Interleukin 1 ◽

Interleukin 1Β ◽

Nmda Receptor Antagonists ◽

Receptor Antagonists ◽

Induced Expression ◽

Interleukin 1 Receptor Antagonist

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Analgesic Interaction between Intrathecal Midazolam and Glutamate Receptor Antagonists on Thermal-induced Pain in Rats

Anesthesiology ◽

10.1097/00000542-199908000-00028 ◽

1999 ◽

Vol 91 (2) ◽

pp. 531-537 ◽

Cited By ~ 28

Author(s):

Tomoki Nishiyama ◽

Laszlo Gyermek ◽

Chingmuh Lee ◽

Sachiko Kawasaki-Yatsugi ◽

Tokio Yamaguchi

Keyword(s):

Receptor Antagonist ◽

Glutamate Receptor ◽

Ampa Receptor ◽

Behavioral Changes ◽

Tail Flick ◽

Receptor Antagonists ◽

Thermal Nociception ◽

Motor Disturbance ◽

Ampa Receptor Antagonist ◽

Glutamate Receptor Antagonists

Background Two major neurotransmitters, gamma-aminobutyric acid (GABA) and the excitatory amino acid, glutamate, may be involved in nociception in the spinal cord. GABA and glutamate receptors may operate in concert to modify signals in the central nervous system. The purpose of this study was to investigate the spinal analgesic interaction between midazolam, a benzodiazepine-GABA(A) receptor agonist, and two glutamate receptor antagonists on acute thermal nociception. Methods Sprague-Dawley rats were implanted with chronic lumbar intrathecal catheters and were tested for their tail withdrawal response by the tail flick test after intrathecal administration of saline, midazolam (1-100 microg), AP-5 (1-30 microg), or YM872 (0.3-30 microg). AP-5 is an N-methyl-D-aspartate (NMDA) receptor antagonist and YM872 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist. The combination of midazolam and the other two agents were also tested by isobolographic analyses. Motor disturbance and behavioral changes were observed. Results Dose-dependent increases in the tail flick latency were observed with midazolam, AP-5, and YM872 with 50% effective dose values of 1.57+/-0.34 (SEM) microg, 5.54+/-0.19 microg, and 1.0+/-0.22 microg, respectively. A potent synergy in analgesia with decreased behavioral changes and motor disturbance was obtained when combining midazolam with AP-5 or YM872. Conclusions Spinally administered midazolam and an NMDA- or an AMPA-receptor antagonist exhibited potent synergistic analgesia on acute thermal nociception in rats. Side effects, shown by behavioral changes and motor disturbance, decreased with the combination of the agents. These results point out an important direction for the study of acute nociception.

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