Interaction among NMDA receptor-, NMDA glycine site- and AMPA receptor antagonists in spinally mediated analgesia.
OBJECTIVE
The NMDA (N-methyl-D-aspartate) receptor antagonists and the NMDA glycine site antagonists given alone have minimal effects on acute nociception. In contrast, the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor antagonists have a major role in acute nociception. We investigated the interactions among these three antagonists in acute nociception.


METHODS
Sprague-Dawley rats (250-300 g) were implanted with chronic lumbar intrathecal catheters and were tested for their thermal withdrawal response using the hot plate test after intrathecal administration of AP-5 (NMDA receptor antagonist), ACEA 1021 (NMDA glycine site antagonist), or ACEA 2085 (AMPA receptor antagonist). The combinations of these three agents were also tested.


RESULTS
Intrathecal administration of ACEA 2085 had a dose dependent analgesic effect while intrathecal AP-5 or ACEA 1021 could not induce dose dependent effect. Co-administration of AP-5 10 microg and ACEA 2085 intrathecally showed no changes in the thermal response latency compared with ACEA 2085 alone. ACEA 1021, 12 microg, and AP-5 showed left-ward shift of the dose effect curve only with small doses of AP-5 (1 microg, 3 microg). Only the smallest dose of ACEA 2085 (0.1 ng) with ACEA 1021 12 microg induced antinociception compared with that of ACEA 2085 alone.


CONCLUSIONS
The combination of the NMDA glycine site antagonist and low doses of the NMDA receptor antagonist or the AMPA receptor antagonist increased the analgesic effect on acute thermal nociception with increased side effects, while the NMDA receptor antagonist and the AMPA receptor antagonist had no such interaction.
Department of Anesthesiology, The University of Tokyo, Japan. NISHIYAMAT-ANE@h.u-tokyo.ac.jp
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Nishiyama
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000698:Analgesia; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000633:toxicity; D005998:Glycine / Q000378:metabolism; D007278:Injections, Spinal; D009043:Motor Activity / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C096637:2-amino-5-phosphono-3-pentenoic acid; C092062:licostinel; D015763:2-Amino-5-phosphonovalerate; D005998:Glycine