Effects of differential modulation of μ-, δ- and κ-opioid systems on bicuculline-induced convulsions in the mouse

Abstract

The present study investigated the effects of μ-, δ- and κ-opioid receptor agonists on seizures produced by blockade of γ-aminobutyric acid (GABA)-mediated synaptic transmission in the mouse. The selective GABA A receptor antagonist bicuculline (1.25–3 mg/kg) given subcutaneously caused dose-dependent clonic–tonic convulsions. These convulsions were potentiated by the prototypic μ-opioid receptor agonist morphine given subcutaneously 20 min prior to a subconvulsive dose of bicuculline. The potentiation by morphine was completely reversed by pretreatment intraventricularly with the selective μ-opioid receptor antagonist β-funaltrexamine (0.5 μg/mouse). Pretreatment intraventricularly with the selective δ-opioid receptor agonists 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aβ-octahydro-quinolino[2,3,3-g]isoquinoline ((−)TAN-67) or [D-Pen 2,5]-enkephalin (DPDPE) showed a dose-dependent increase in the incidence of convulsions. Pretreatment with naltrindole (2 mg/kg, s.c.), a selective δ-opioid receptor antagonist, abolished the enhancement of the bicuculline-induced convulsions by DPDPE. In contrast, pretreatment with the selective κ-opioid receptor agonist U-50,488H (0.6–80 mg/kg, subcutaneously or 25–100 μg/mouse, intraventricularly) produced a dose-dependent suppression of the bicuculline-induced convulsions. The inhibitory effect of U-50,488H was completely blocked by pretreatment subcutaneously with nor-binaltorphimine (5 mg/kg), a selective κ-opioid receptor antagonist. This study demonstrates that activation of both μ- and δ-opioid receptors increases the incidence of convulsions produced by blockade of GABA-mediated synaptic transmission, while stimulation of κ-opioid receptors has an anticonvulsive effect.