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.

• Authors: Lakeisha A Lewter, Lalit K Golani, James M Cook, Jun-Xu Li
• Journal: Behavioural pharmacology (Behav Pharmacol) Vol. 32 Issue 4 Pg. 345-350 (06 01 2021) ISSN: 1473-5849 [Electronic] England
• PMID: 33290344 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• 3-propoxy-beta-carboline
• Analgesics
• Carbolines
• GABA Modulators
• GABA-A Receptor Antagonists
• Pharmaceutical Vehicles
• Receptors, GABA-A
• Benzodiazepines
• tert-butyl beta-carboline-3-carboxylate
• Midazolam

Topics

• Analgesics (pharmacology)
• Animals
• Benzodiazepines (pharmacology)
• Carbolines (pharmacology)
• Drug Therapy, Combination (methods)
• Drug Tolerance (physiology)
• GABA Modulators
• GABA-A Receptor Antagonists (pharmacology)
• Midazolam (pharmacology)
• Pain Threshold (drug effects)
• Pharmaceutical Vehicles (pharmacology)
• Rats
• Receptors, GABA-A (metabolism)