Riluzole, a glutamate release inhibitor, induces loss of righting reflex, antinociception, and immobility in response to noxious stimulation in mice.
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.
Irifune
Masahiro
M
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
Kikuchi
Nobuhito
N
Saida
Takuya
T
Takarada
Tohru
T
Shimizu
Yoshitaka
Y
Endo
Chie
C
Morita
Katsuya
K
Dohi
Toshihiro
T
Sato
Tomoaki
T
Kawahara
Michio
M
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
D000700:Analgesics; D018698:Glutamic Acid; D019782:Riluzole