Participation of the GABA/benzodiazepine receptor and the NO-cyclicGMP pathway in the "antinociceptive-like effects" of diazepam.
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, Nomega-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.
Jiménez-Velázquez
Guadalupe
G
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.
López-Muñoz
Francisco Javier
FJ
Fernández-Guasti
Alonso
A
D000700:Analgesics; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis / Q000502:physiology*; D003975:Diazepam / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
D000700:Analgesics; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D007191:Indazoles; D020030:Nitric Oxide Donors; D011963:Receptors, GABA-A; D009569:Nitric Oxide; D001120:Arginine; D052248:Nitric Oxide Synthase Type I; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D003975:Diazepam; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester