TY - JOUR
T1 - Cross-sensitivity between isoflurane and diazepam
T2 - Evidence from a bidirectional tolerance study in mice
AU - Flaishon, Ron
AU - Halpern, Pinchas
AU - Sorkine, Patrick
AU - Weinbroum, Avraham
AU - Leschiner, Svetlana
AU - Szold, Oded
AU - Rudick, Valery
AU - Gavish, Moshe
PY - 1999/1/9
Y1 - 1999/1/9
N2 - We examined in mice the effect of chronic diazepam treatment on the sensitivity to isoflurane, and that of repeated isoflurane exposure on the sensitivity 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; group 3, exposed to 3% isoflurane for 25 min twice daily; and group 4, untreated controls. After 14 days the effect of the treatment was assessed. Twenty-four hours after the last 10 mg/kg diazepam treatment, groups 1 and 2 received diazepam, 5 mg/kg i.p., and were subjected to the horizontal wire test (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 isoflurane. Diazepam-treated mice (group 1) lost the HWT at 0.7 ± 0.7%, compared 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% isoflurane vs. 0.87 ± 0.06% in group 2 (P < 0.01); the ED50 was 0.93% vs. 0.82%. Recovery time was 175 ± 161 s in group 1 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 concentrations 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 s in groups 3 and 4 (P < 0.09). Diazepam, 3 mg/kg i.p. administered to groups 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 both diazepam and isoflurane caused reduced sensitivity to each drug separately, as well as to the other drug. This finding may strengthen the theory that inhalational anesthetics may act via the same mechanism as the benzodiazepines.
AB - We examined in mice the effect of chronic diazepam treatment on the sensitivity to isoflurane, and that of repeated isoflurane exposure on the sensitivity 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; group 3, exposed to 3% isoflurane for 25 min twice daily; and group 4, untreated controls. After 14 days the effect of the treatment was assessed. Twenty-four hours after the last 10 mg/kg diazepam treatment, groups 1 and 2 received diazepam, 5 mg/kg i.p., and were subjected to the horizontal wire test (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 isoflurane. Diazepam-treated mice (group 1) lost the HWT at 0.7 ± 0.7%, compared 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% isoflurane vs. 0.87 ± 0.06% in group 2 (P < 0.01); the ED50 was 0.93% vs. 0.82%. Recovery time was 175 ± 161 s in group 1 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 concentrations 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 s in groups 3 and 4 (P < 0.09). Diazepam, 3 mg/kg i.p. administered to groups 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 both diazepam and isoflurane caused reduced sensitivity to each drug separately, as well as to the other drug. This finding may strengthen the theory that inhalational anesthetics may act via the same mechanism as the benzodiazepines.
KW - Benzodiazepine
KW - Inhaled anesthetic
KW - Isoflurane
KW - Mechanism of action
KW - Reduced sensitivity
KW - Tolerance
UR - http://www.scopus.com/inward/record.url?scp=0033537289&partnerID=8YFLogxK
U2 - 10.1016/S0006-8993(98)01120-2
DO - 10.1016/S0006-8993(98)01120-2
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AN - SCOPUS:0033537289
SN - 0006-8993
VL - 815
SP - 287
EP - 293
JO - Brain Research
JF - Brain Research
IS - 2
ER -