I am a
Home I AM A Search Login

Papers of the Week


Papers: 5 Dec 2020 - 11 Dec 2020


Animal Studies, Pharmacology/Drug Development


2020 Dec 07


Behav Pharmacol

Blockade of α1 subtype GABAA receptors attenuates the development of tolerance to the antinociceptive effects of midazolam in rats.

Abstract

Benzodiazepines bind to and act on α1-3 and α5-containing GABAA receptors. Previous studies suggest that different GABAA receptor α-subtypes mediate the various behavioral effects of benzodiazepines, which raises the possibility of combining benzodiazepines with subtype-selective GABAA receptor antagonists to improve the therapeutic profiles of benzodiazepines. This study examined the GABAA receptor subtype mediation of the tolerance to midazolam-induced antinociception in rats. Midazolam (3.2 mg/kg) significantly reduced the locomotion in rats which was prevented by the selective α1-preferring GABAA receptor antagonist β-carboline-3-carboxylate-t-butyl ester (βCCt) (3.2 mg/kg). Midazolam increased the paw withdrawal threshold as tested by the von Frey filament assay in the complete Freund's adjuvant-induced inflammatory pain model in rats, and this effect was not altered by βCCt or another α1-preferring GABAA receptor antagonist 3-propoxy-β-carboline hydrochloride (3PBC). Repeated treatment with midazolam in combination with vehicle, βCCt or 3PBC (twice daily) for 7 days led to a progressive increase of the ED50 values in the midazolam- and vehicle-treated rats, but not in other rats, suggesting the development of tolerance to midazolam but not to the combination of midazolam with α1-preferring GABAA receptor antagonists. These results suggest the essential role of the α1-subtype of GABAA receptors in mediating the development of tolerance to midazolam-induced antinociceptive effects and raise the possibility of increasing therapeutic profiles of benzodiazepines by selectively blocking specific α-subtypes of GABAA receptors.