ANESTHETIC PROPERTIES OF RILUZOLE (54274-RP), A NEW INHIBITOR OF GLUTAMATE NEUROTRANSMISSION

It has been suggested that some anesthetic agents could exert their hypnotic/anesthetic effects by selectively blocking receptors involved in the central excitatory neurotransmission mediated by glutamate. In the present study, we analyzed whether riluzole (54274 RP), a novel compound that inhibits both the release and some postsynaptic effects of glutamate in some brain structures, has anesthetic properties in rats. For this purpose, we investigated whether 1) riluzole administered intraperitoneally (ip) at doses ranging from 2.5 to 45 mg/kg induces loss of righting reflex (LRR); 2) riluzole (2.5 and 5 mg/kg) prolongs sleep-times induced by either ketamine (30 or 80 mg/kg ip) or thiopental (25 or 35 mg/kg ip); 3) a 5-mg/kg subanesthetic riluzole dose affects the minimum alveolar concentration of halothane (MACh). Onset of drug action was defined as the period of time from the ip injection to LRR. Sleep-time was considered the period of time from LRR to restoration of righting reflex. Riluzole at doses greater than 15 mg/kg was able to induce LRR (riluzole dose for which LRR was achieved in 50% of the rats [ED50 = 25.6 mg/kg]). A positive correlation was found between the dose of riluzole and sleep-time (r = 0.92, P < 0.001). A 5-mg/kg (but not 2.5-mg/kg) riluzole dose significantly prolonged sleep-times induced by both ketamine (30 and 80 mg/kg) and thiopental (25 but not 35 mg/kg). Moreover, a 5-mg/kg riluzole dose produced a significant reduction in MACh (0.63 +/- 0.03 vs. 1.05 +/- 0.02 vol% in controls, mean +/- SEM, P < 0.01), whereas a subanesthetic ip dose (2 mg/kg) of the N-methyl-D-aspartate receptor antagonist MK-801 also induced a marked decrease in MACh (0.52 +/- 0.04 vs. 1.05 +/- 0.02 vol% for control values, P < 0.01). These results demonstrate that riluzole exerts an anesthetic action and is able to potentiate anesthesia induced by different receptor-mediated anesthetic agents in rats. These findings suggest that alteration of glutamate neurotransmission may be involved in some anesthetic mechanisms.