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.
Wynn
R L
RL
Department of Pharmacology, Dental School, University of Maryland, Baltimore 21201.
Bergman
S A
SA
Rudo
F G
FG
Leventer
M
M
D000522:Alphaprodine / Q000494:pharmacology; D000700:Analgesics; D000818:Animals; D003782:Dental Pulp / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D005283:Fentanyl / Q000494:pharmacology; D008297:Male; D008614:Meperidine / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D009118:Muscimol / Q000494:pharmacology; D011817:Rabbits; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000502:physiology*; D017450:Receptors, Opioid, mu; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000700:Analgesics; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D000522:Alphaprodine; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D008614:Meperidine; D003975:Diazepam; D005283:Fentanyl