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Selective blockade of N-methyl-d-aspartate channels in combination with dopamine receptor antagonism induces loss of the righting reflex in mice, but not immobility

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Abstract

Rationale

The selective N-methyl-d-aspartate (NMDA) channel blocker MK-801 is known to induce no loss of the righting reflex (LORR) and to stimulate catecholaminergic (CAergic) neurons in rodents, playing a crucial role in arousal.

Objectives

We examined whether MK-801 in combination with CA receptor ligands, which inhibit CAergic neuronal activities, could induce anesthesia including LORR.

Methods

All drugs were administered systemically to mice. To assess anesthesia, three different behaviors were used: loss of nociceptive response (analgesia in the free-moving state without LORR), LORR, and loss of movement in response to noxious stimulation (immobility under LORR).

Results

A very large dose of MK-801 (50 mg/kg) induced neither analgesia nor LORR. In contrast, MK-801 in combination with a small dose of the dopamine (DA) receptor antagonist haloperidol (0.2 mg/kg) dose-dependently produced LORR with a 50 % effective dose (ED50) of 1.6 (0.9–3.0; 95 % confidence limit) mg/kg, but not immobility. The α2-adrenoceptor agonist dexmedetomidine induced not only analgesia, but also immobility in animals treated with MK-801 (5 mg/kg) plus haloperidol (0.2 mg/kg), which then lost their righting reflex. The ED50 value of 0.26 (0.10–0.66) mg/kg (various doses of dexmedetomidine plus a fixed dose of MK-801 and haloperidol) for immobility was approximately three-fold larger than that of 0.09 (0.03–0.23) mg/kg (dexmedetomidine plus vehicle saline) for analgesia. This may occur, as LORR induced by MK-801 plus haloperidol inhibits the pain suppression system. The other ligands had little or no effect.

Conclusions

The DAergic stimulant actions of MK-801 may mask its LORR effects by NMDA channel blockade.

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Acknowledgments

This study was supported in part by Grant-in-Aid No. 18592037 for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. We thank Medical English Service Corp. (Kyoto, Japan) for English language editing.

Conflict of interest

Authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Dental Anesthesiology, Program of Dental Sciences, Integrated Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan

    Nobuhito Kikuchi, Masahiro Irifune & Yoshitaka Shimizu

  2. Section of Dental Anesthesiology, Department of Oral & Maxillofacial Surgery and Oral Medicine, Hiroshima University Hospital, Hiroshima, Japan

    Keita Yoshida

  3. Department of Cellular and Molecular Pharmacology, Program of Dental Sciences, Basic Life Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan

    Katsuya Morita & Takashi Kanematsu

  4. Department of Pharmacology, Program of Pharmaceutical Sciences, Applied Life Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan

    Norimitsu Morioka & Yoshihiro Nakata

  5. Department of Molecular and Pharmacological Neuroscience, Program of Medical Sciences, Basic Life Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan

    Norio Sakai

Authors
  1. Nobuhito Kikuchi
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  2. Masahiro Irifune
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  8. Yoshihiro Nakata
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  9. Norio Sakai
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Correspondence to Masahiro Irifune.

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Kikuchi, N., Irifune, M., Shimizu, Y. et al. Selective blockade of N-methyl-d-aspartate channels in combination with dopamine receptor antagonism induces loss of the righting reflex in mice, but not immobility. Psychopharmacology 232, 39–46 (2015). https://doi.org/10.1007/s00213-014-3634-y

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  • DOI: https://doi.org/10.1007/s00213-014-3634-y

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