Evidence For Involvement Of GABA_A Receptors In Antinociceptive Effects Of Diazepam In Mice

As one of benzodiazepine drugs, diazepam has a wide spectrum of pharmacological effects in clinic and usually used as treatment of anxiety, epilepsies sleep disorders and muscle rigor and so on. Most of benzodiazepines effects are mediated by interaction with benzodiazepine binding site of GABA_A receptors. Recently, several lines of evidence had indicated that neurotransmission involving the GABAergic system plays an important role in the modulation of pain pathways. Besides the effect of diazepam on pain was unclear, we investigated its effects and approached the mechanisms on pain with two different nocicepiton tests.The antinociceptive effects of diazepam were investigated using tail-immersion test and the formalin test in mice. Intraperitoneal (i.p.) injection of diazepam (1 mg/kg) significantly increased the tail-withdrawal latency in the tail-immersion test. The diazepam induced prolongation of tail-withdrawal latency could be reversed by systemic administrations of flumazenil(a special antagonist of benzodiazepine binding site associated with GABA_A receptors), bicuculline(a competitive antagonist of GABA_A receptor), and picrotoxin (a blocker of chlorine ion channel), respectively. In the formalin test, low doses of diazepam (0.5 mg/kg and 0.25 mg/kg, i.p.) markedly decreased the cumulative licking/biting time of the second phase (10-45 min), whereas the first phase (0-10 min) was not affected. In addition, the reduction of the cumulative licking/biting time of the second phase was abolished by pretreatment with bicuculline or picrotoxin. Therefore, these data indicated that intraperitoneal administration of diazepam could produce antinociceptive effects, and endogenous GABA and GABA_A receptors may be involved in the antinociception of diazepam.