Canadian Journal of Anaesthesia

, Volume 54, Issue 12, pp 998–1005

MK-801 enhances gabaculine-induced loss of the righting reflex in mice, but not immobility

  • Masahiro Irifune
  • Sohtaro Katayama
  • Tohru Takarada
  • Yoshitaka Shimizu
  • Chie Endo
  • Takashi Takata
  • Katsuya Morita
  • Toshihiro Dohi
  • Tomoaki Sato
  • Michio Kawahara
Reports Of Original Investigations

Abstract

Purpose: γ-Aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors are important targets for anesthetic action at thein vitro cellular level. Gabaculine is a GABA-transaminase inhibitor that increases endogenous GABA in the brain, and enhances GABA activity. We have recently shown that unconsciousness is associated with the enhanced GABA activity due to gabaculine, but that immobility is not. MK-801 is a selective NMDA channel blocker. In this study, we examined behaviourally whether gabaculine in combination with MK-801 could produce these components of the general anesthetic state. We further compared the effect of MK-801 with ketamine, another NMDA channel blocker.

Methods: All drugs were administered intraperitoneally to adult male ddY mice. To assess the general anesthetic components, two endpoints were used. One was loss of the righting reflex (LORR; as a measure of unconsciousness) and the other was loss of movement in response to tail-clamp stimulation (as a measure of immobility).

Results: Large doses of MK-801 alone (10–50 mg·kg−1) induced neither LORR nor immobility in response to noxious stimulation. However, even a small dose (0.2 mg·kg−1) significantly enhanced gabaculine-induced LORR (P<0.05), although gabaculine in combination with MK-801 (0.2–10 mg·kg−1) produced no immobility. However, gabaculine plus a subanesthetic dose of ketamine (30 mg·kg−1), which acts on NMDA, opioid and nicotinic acetylcholine receptors and neuronal Na+ channels, suppressed the pain response, but did not achieve a full effect. Ketamine alone dose-dependently produced both LORR and immobility.

Conclusion: These findings suggest that gabaculine-induced LORR is modulated by blocking NMDA receptors, but that immobility is not mediated through GABA or NMDA receptors.

Le MK-801 accentue la perte du réflexe de redressement provoqué par la gabaculine chez les souris, mais pas l’immobilité

Résumé

Objectif: Les récepteurs GABA (acide gamma-aminobutyrique) et NMDA (N-méthyl-D-aspartate) constituent d’importantes cibles pour l’action des anesthésiques au niveau cellulaire in vitro. La ga-baculine est un inhibiteur des GABA-transaminases qui augmente le GABA endogène dans le cerveau, et stimule l’activité GABA. Nous avons récemment démontré que la perte de conscience est associée à l’activité GABA stimulée par la gabaculine, mais que l’immobilité ne l’est pas. Le MK-801 est un bloqueur sélectif du canal NMDA. Dans cette étude, nous avons examiné si la gabaculine combinée à du MK-801 pouvait produire ces composantes de l’état d’anesthésie générale au niveau comportemental. Nous avons également comparé l’effet du MK-801 à celui de la kétamine, un autre bloqueur du canal NMDA.

Méthode: Tous les médicaments ont été administrés à des souris mâles adultes ddY par voie intrapéritonéale. Deux paramètres ont été utilisés afin d’évaluer les composantes de l’anesthésie générale. L’un était la perte du réflexe de redressement (LORR — loss of righting reflex ; pour mesurer la perte de conscience), et l’autre l’absence de mouvement en réaction à la stimulation d’une pince à la queue (pour mesurer l’immobilité).

Résultats: D’importantes doses de MK-801 seul (10–50 mg·kg−1) n’ont provoqué ni LORR ni l’immobilité en réaction à une stimulation nociceptive. Toutefois, une dose même faible (0.2 mg·kg−1) a significativement accentué le LORR provoqué par la gabaculine (P<0,05), bien que la gabaculine associée à du MK-801 (0,2–10 mg·kg−1)n’ait pas provoqué d’immobilité. Cependant, la gabaculine additionnée d’une dose sous-anesthésique de kétamine (30 mg·kg−1),laquelle agit sur les récepteurs NMDA, opiacés et cholinergiques nicotiniques ainsi que sur les canaux Na+, a supprimé la réaction douloureuse, mais n’a pas eu un effet complet. La kétamine seule a provoqué LORR et immobilité, de façon dose-dépendante.

Conclusion: Ces résultats suggèrent que le LORR provoqué par la gabaculine est modulé en bloquant les récepteurs NMDA, mais que l’immobilité n’est pas médiée par les récepteurs GABA ou NMDA.

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Copyright information

© Canadian Anesthesiologists 2007

Authors and Affiliations

  • Masahiro Irifune
    • 1
  • Sohtaro Katayama
    • 1
  • Tohru Takarada
    • 1
  • Yoshitaka Shimizu
    • 1
  • Chie Endo
    • 1
  • Takashi Takata
    • 2
  • Katsuya Morita
    • 3
  • Toshihiro Dohi
    • 3
  • Tomoaki Sato
    • 4
  • Michio Kawahara
    • 1
  1. 1.Department of Dental Anesthesiology, Division of Clinical Medical Science, Programs for Applied BiomedicineGraduate School of Biomedical Sciences, Hiroshima UniversityHiroshimaJapan
  2. 2.the Department of Oral Maxillofacial Pathobiology, Division of Frontier Medical ScienceGraduate School of Biomedical Sciences, Hiroshima UniversityHiroshimaJapan
  3. 3.the Department of Dental Pharmacology, Division of Integrated Medical Science, Programs for Biomedical ResearchGraduate School of Biomedical Sciences, Hiroshima UniversityHiroshimaJapan
  4. 4.the Department of Applied PharmacologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan

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