Participation of the GABA/benzodiazepine receptor and the NO-cyclicGMP pathway in the "antinociceptive-like effects" of diazepam |
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Authors: | Jiménez-Velázquez Guadalupe López-Muñoz Francisco Javier Fernández-Guasti Alonso |
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Affiliation: | Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Sede Sur, Calz. de los Tenorios 235, Col. Granjas Coapa, C.P. 14330, México D.F., Mexico. |
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Abstract: | The mechanism of action underlying the "analgesic activity" of diazepam remains unclear. In this study, the possible participation of the GABA/benzodiazepine receptor and the nitric oxide-cyclic GMP (NO-cGMP) pathway was assessed utilizing the pain-induced functional impairment model in the rat (PIFIR). Nociception was induced by an intra-articular injection of 15% uric acid. Diazepam (1 and 2 mg/kg, i.p.) reversed the dysfunction induced by uric acid. Flumazenil (10 mg/kg, i.p.), a GABA/benzodiazepine receptor antagonist, abolished the "antinociceptive-like effect" of diazepam (at 2 mg/kg). The "antinociceptive-like effect" of diazepam (at 2 mg/kg) was antagonized by the non-selective nitric oxide synthase (NOS) inhibitor, N(omega)-l-nitro-arginine methyl ester hydrochloride (l-NAME, 5 mg/kg, s.c.) (but not by its inactive isomer), and by the selective neuronal NOS inhibitor, 7-nitroindazole (7-NI, 1 mg/kg, i.p). While, the NO precursor, l-arginine (125 mg/kg, s.c.), but not d-arginine (125 mg/kg, s.c.), increased the "antinociceptive-like effect" of a non-effective dose of diazepam (1 mg/kg). Methylene blue (10 mg/kg, i.p.), a guanylate cyclase inhibitor, also prevented the "antinociceptive-like effect" of diazepam (at 2 mg/kg). These results suggest that the GABA/benzodiazepine receptor and the NO-cGMP pathway participate in the "antinociceptive-like effect" of diazepam. |
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Keywords: | Diazepam Antinociception Nitric oxide Cyclic GMP Flumazenil smallcaps" >L-NAME 7-nitroindazole smallcaps" >L-arginine Methylene blue PIFIR model |
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