title: 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.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Kikuchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Irifune
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Keita
authors.initials: K
authors.lastname: Yoshida
authors.forename: Katsuya
authors.initials: K
authors.lastname: Morita
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanematsu
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Morioka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakata
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D018492:Dopamine Antagonists / Q000008:administration & dosage*; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D006220:Haloperidol / Q000008:administration & dosage; D007103:Immobilization / Q000502:physiology; D008297:Male; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D057897:Reflex, Righting / Q000187:drug effects* / Q000502:physiology
chemical_list: D018492:Dopamine Antagonists; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D006220:Haloperidol