GABAmimetics diminish antinociception of meperidine under conditions which enhance other opioid mu-agonists.

This study investigated the effects of pretreatment with muscimol (GABA-agonist) or diazepam (indirect GABAmimetic) on i.v. meperidine, fentanyl, alphaprodine and morphine, using rabbit tooth pulp and mouse hot plate assays. A previous study reported that the ED50 values for fentanyl in rabbits were significantly lowered by 0.25 mg/kg of muscimol (13.8 to 1.8 micrograms/kg) and by 1.5 mg/kg of diazepam (13.1 to 1.1 micrograms/kg). ED50 values for meperidine in rabbits in this study were increased by muscimol (1.2 to 3.2 mg/kg) and diazepam (1.5 to 3.1 mg/kg). ED50 values for fentanyl in mice were significantly lowered by 0.25 mg/kg of muscimol (23.0 to 8.9 micrograms/kg) and 1.0 mg/kg of diazepam (23.3 to 12.8 micrograms/kg). ED50 values for meperidine in mice were significantly increased by muscimol (2.1 to 5.0 mg/kg) and diazepam (2.0 to 4.8 mg/kg). ED50 values for alphaprodine and morphine were significantly lowered by muscimol and diazepam in mice. A higher dose of muscimol (1.0 mg/kg) had no effect on the ED50 values of meperidine in mice. The antinociception of a submaximal dose of meperidine in rabbits was significantly reduced by a 10 min pretreatment with i.v. diazepam (1.5 mg/kg) at 15, 20, 30 and 45 min after i.v. meperidine. The antinociception of a submaximal dose of fentanyl in rabbits was significantly increased by a 10 min pretreatment with i.v. diazepam (1.5 mg/kg) at 5, 10, 15 and 20 min after i.v. fentanyl. Pretreatment with 0.1 mg/kg of scopolamine enhanced the antinociceptive effect of a submaximal dose of fentanyl in both animal models. Diazepam reduced the antinociception produced by the combination scopolamine-fentanyl to that of fentanyl-vehicle control in both animal models. Pretreatment with 0.1 mg/kg of scopolamine did not change the magnitude of antinociception of a submaximal dose of meperidine in rabbits. Since meperidine possesses inherent anticholinergic activity, it is suggested that this anticholinergic activity may be involved in the reduction effects by muscimol and diazepam.