High-dose flumazenil potentiates the hypnotic activity of propofol, but not that of thiopental, in ddY mice

Background: Flumazenil is a specific benzodiazepine agonist, which is reported to have a partial benzodiazepine agonist-like effect at a high dose. This study investigated the effects of flumazenil and midazolam on the hypnotic dose of propofol and thiopental in ddY mice, using a behavioral model. Methods: Mice were given either propofol or thiopental intravenously to induce hypnosis, which was defined as a loss of the righting reflex. The mice were pre-treated with flumazenil (0.05, 0.1, or 0.2 mg kg(-1)) or midazolam (0.1 or 0.2 mg kg(-1)), and given propofol or thiopental after a 30-s delay. Results: Pre-treatment with flumazenil (0.1 or 0.2 mg kg(-1)) significantly decreased the hypnotic dose of propofol compared to the control group (9.3 +/-0.39 [8.5-10.0] or 9.0 +/-0.28 [8.5-9.6] vs. 10.8 +/-0.42 [9.9-11.6] mg kg(-1) (ED50+/- SEM and [95% confidence interval]) P <0.05), but not that of thiopental (9.1 +/-0.30 [8.5-9.7] with 0.2 mg kg(-1) flumazenil vs. 9.3 +/-0.42 [8.4-10.1] mg kg(-1) with saline). Midazolam reduced the hypnotic dose of both propofol and thiopental. Flumazenil antagonized the potentiating effect of midazolam (0.2 mg kg(-1)) on the hypnotic activity of propofol. Conclusions: These results suggest that the hypnotic activity of propofol is potentiated by the partial agonist activity of flumazenil in ddY mice.