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

Research output: Contribution to journalArticle

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Abstract

Purpose: γ-Aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors are important targets for anesthetic action at the in 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.

Original languageEnglish
Pages (from-to)998-1005
Number of pages8
JournalCanadian Journal of Anesthesia
Volume54
Issue number12
DOIs
Publication statusPublished - Jan 1 2007
Externally publishedYes

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Righting Reflex
Dizocilpine Maleate
gamma-Aminobutyric Acid
Ketamine
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
General Anesthetics
Unconsciousness
4-Aminobutyrate Transaminase
Aminobutyrates
Nicotinic Receptors
gabaculine
Opioid Analgesics
Anesthetics
Tail
Pain
Brain

All Science Journal Classification (ASJC) codes

  • Anesthesiology and Pain Medicine

Cite this

MK-801 enhances gabaculine-induced loss of the righting reflex in mice, but not immobility. / Irifune, Masahiro; Katayama, Sohtaro; Takarada, Tohru; Shimizu, Yoshitaka; Endo, Chie; Takata, Takashi; Morita, Katsuya; Dohi, Toshihiro; Sato, Tomoaki; Kawahara, Michio.

In: Canadian Journal of Anesthesia, Vol. 54, No. 12, 01.01.2007, p. 998-1005.

Research output: Contribution to journalArticle

Irifune, M, Katayama, S, Takarada, T, Shimizu, Y, Endo, C, Takata, T, Morita, K, Dohi, T, Sato, T & Kawahara, M 2007, 'MK-801 enhances gabaculine-induced loss of the righting reflex in mice, but not immobility', Canadian Journal of Anesthesia, vol. 54, no. 12, pp. 998-1005. https://doi.org/10.1007/BF03016634
Irifune, Masahiro ; Katayama, Sohtaro ; Takarada, Tohru ; Shimizu, Yoshitaka ; Endo, Chie ; Takata, Takashi ; Morita, Katsuya ; Dohi, Toshihiro ; Sato, Tomoaki ; Kawahara, Michio. / MK-801 enhances gabaculine-induced loss of the righting reflex in mice, but not immobility. In: Canadian Journal of Anesthesia. 2007 ; Vol. 54, No. 12. pp. 998-1005.
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abstract = "Purpose: γ-Aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors are important targets for anesthetic action at the in 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.",
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AU - Shimizu, Yoshitaka

AU - Endo, Chie

AU - Takata, Takashi

AU - Morita, Katsuya

AU - Dohi, Toshihiro

AU - Sato, Tomoaki

AU - Kawahara, Michio

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N2 - Purpose: γ-Aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors are important targets for anesthetic action at the in 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.

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