Blockade of α1 subtype GABAA receptors attenuates the development of tolerance to the antinociceptive effects of midazolam in rats
| Autor: | Lakeisha A. Lewter, James M. Cook, Lalit K. Golani, Jun-Xu Li |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Pain Threshold
Hydrochloride Midazolam Pharmacology Article Benzodiazepines 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals GABA-A Receptor Antagonists GABA Modulators Receptor ED50 Analgesics GABAA receptor Antagonist Drug Tolerance Receptors GABA-A Rats 030227 psychiatry Blockade Psychiatry and Mental health Nociception chemistry Drug Therapy Combination Pharmaceutical Vehicles 030217 neurology & neurosurgery Carbolines medicine.drug |
| Zdroj: | Behav Pharmacol |
| ISSN: | 0955-8810 |
| DOI: | 10.1097/fbp.0000000000000614 |
| Popis: | Benzodiazepines bind to and act on α1–3 and α5-containing GABA(A) receptors. Previous studies suggest that different GABA(A) receptor α-subtypes mediate the various behavioral effects of benzodiazepines, which raises the possibility of combining benzodiazepines with subtype-selective GABA(A) receptor antagonists to improve the therapeutic profiles of benzodiazepines. This study examined the GABA(A) 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 GABA(A) 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 GABA(A) 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 progressive increase of the ED(50) 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 GABA(A) receptor antagonists. These results suggest the essential role of the α1-subtype of GABA(A) 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 GABA(A) receptors. |
| Databáze: | OpenAIRE |
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