title: Riluzole, a glutamate release inhibitor, induces loss of righting reflex, antinociception, and immobility in response to noxious stimulation in mice.
abstract: BACKGROUND
  The general anesthetic state comprises behavioral and perceptual components, including amnesia, unconsciousness, analgesia, and immobility. In vitro, glutamatergic excitatory neurons are important targets for anesthetic action at the cellular and microcircuits levels. Riluzole (2-amino-6-[trifluoromethoxy]benzothiazole) is a neuroprotective drug that inhibits glutamate release from nerve terminals in the central nervous system. Here, we examined in vivo the ability of riluzole to produce components of the general anesthetic state through a selective blockade of glutamatergic neurotransmission.
  
  
  METHODS
  Riluzole was administered intraperitoneally in adult male ddY mice. To assess the general anesthetic components, three end-points were used: 1) loss of righting reflex (LORR; as a measure of unconsciousness), 2) loss of movement in response to noxious stimulation (as a measure of immobility), and 3) loss of nociceptive response (as a measure of analgesia).
  
  
  RESULTS
  The intraperitoneal administration of riluzole induced LORR in a dose-dependent fashion with a 50% effective dose value of 27.4 (23.3-32.2; 95% confidence limits) mg/kg. The behavioral and microdialysis studies revealed that time-course changes in impairment and LORR induced by riluzole corresponded with decreased glutamate levels in the mouse brain. This suggests that riluzole-induced LORR (unconsciousness) could result, at least in part, from its ability to decrease brain glutamate concentrations. Riluzole dose-dependently produced not only LORR, but also loss of movement in response to painful stimulation (immobility), and loss of nociceptive response (analgesia) with 50% effective dose values of 43.0 (37.1-49.9), and 10.0 (7.4-13.5) mg/kg, respectively. These three dose-response curves were parallel, suggesting that the behavioral effects of riluzole may be mediated through a common site of action.
  
  
  CONCLUSIONS
  These findings suggest that riluzole-induced LORR, immobility, and antinociception appear to be associated with its ability to inhibit glutamatergic neurotransmission in the central nervous system.
authors.affiliation: Department of Dental Anesthesiology, Division of Clinical Medical Science, Programs for Applied Biomedicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. mirifun@hiroshima-u.ac.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Irifune
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Kikuchi
authors.forename: Takuya
authors.initials: T
authors.lastname: Saida
authors.forename: Tohru
authors.initials: T
authors.lastname: Takarada
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Chie
authors.initials: C
authors.lastname: Endo
authors.forename: Katsuya
authors.initials: K
authors.lastname: Morita
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Dohi
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Sato
authors.forename: Michio
authors.initials: M
authors.lastname: Kawahara
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism*; D007103:Immobilization / Q000379:methods; D008297:Male; D051379:Mice; D009068:Movement / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D010812:Physical Stimulation / Q000009:adverse effects / Q000379:methods; D012018:Reflex / Q000187:drug effects* / Q000502:physiology; D019782:Riluzole / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D018698:Glutamic Acid; D019782:Riluzole