Cross-sensitivity between isoflurane and diazepam: evidence from a bidirectional tolerance study in mice

We examined in mice the effect of chronic diazepam treatment on the sensiti vity to isoflurane, and that of repeated isoflurane exposure on the sensiti vity to diazepam. Mice were divided into four groups: group 1, treated with diazepam, 10 mg/kg i.p. twice daily; group 2, vehicle-treated controls; gr oup 3, exposed to 3% isoflurane for 25 min twice daily; and group 4, untrea ted controls. After 14 days the effect of the treatment was assessed. Twent y-four hours after the last 10 mg/kg diazepam treatment, groups 1 and 2 rec eived diazepam, 5 mg/kg i.p., and were subjected to the horizontal wire tes t (HWT). All control mice but only 10% of the diazepam-treated mice failed the HWT. Groups 1 and 2 were then exposed to increasing concentrations of i soflurane. Diazepam-treated mice (group 1) lost the HWT at 0.7 +/- 0.7%, co mpared with 0.6 +/- 0.1% in controls (group 2) (P < 0.001); the ED50 was 0. 75% vs. 0.65%. Group 1 mice lost the righting reflex at 0.94 +/- 0.07% isof lurane vs. 0.87 +/- 0.06% in group 2 (P < 0.01); the ED50 was 0.93% vs. 0.8 2%. Recovery time was 175 +/- 161 s in group I vs. 343 +/- 275 s in group 2 (P < 0.02). Twenty-four hours after the last of the repeated exposures to isoflurane, we examined the responses of groups 3 and 4 to increasing conce ntrations of isoflurane. Mice in group 3 lost the righting reflex at 1.0 +/ - 0.06% isoflurane vs. 0.9 +/- 0.04% in controls (group 4) (P < 0.001); the ED50 was 0.96% vs. 0.85%. Recovery time was 113 +/- 124 s vs. 208 +/- 126 a in groups 3 and 4 (P < 0.09). Diazepam, 3 mg/kg i.p. administered to grou ps 3 and 4, caused loss of the HWT reflex in 33% of group 3 mice and in 82% of controls (group 4) (P < 0.001). It appears that prolonged exposure to b oth diazepam and isoflurane caused reduced sensitivity to each drug separat ely, as well as to the other drug. This finding may strengthen the theory t hat inhalational anesthetics may act via the same mechanism as the benzodia zepines. (C) 1999 Published by Elsevier Science B.V. All rights reserved.