Effects of differential modulation of mu-, delta- and kappa-opioid systems on bicuculline-induced convulsions in the mouse

Brain Res. 2000 Apr 17;862(1-2):120-6. doi: 10.1016/s0006-8993(00)02096-5.


The present study investigated the effects of micro-, delta- and kappa-opioid receptor agonists on seizures produced by blockade of gamma-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 mu-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 mu-opioid receptor antagonist beta-funaltrexamine (0.5 microgram/mouse). Pretreatment intraventricularly with the selective delta-opioid receptor agonists 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12abeta-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 delta-opioid receptor antagonist, abolished the enhancement of the bicuculline-induced convulsions by DPDPE. In contrast, pretreatment with the selective kappa-opioid receptor agonist U-50,488H (0.6-80 mg/kg, subcutaneously or 25-100 microgram/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 kappa-opioid receptor antagonist. This study demonstrates that activation of both mu- and delta-opioid receptors increases the incidence of convulsions produced by blockade of GABA-mediated synaptic transmission, while stimulation of kappa-opioid receptors has an anticonvulsive effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
  • Analgesics / pharmacology
  • Analgesics, Non-Narcotic / pharmacology
  • Analgesics, Opioid / pharmacology
  • Animals
  • Bicuculline*
  • Brain Chemistry / drug effects
  • Brain Chemistry / physiology
  • Convulsants*
  • Enkephalin, D-Penicillamine (2,5)- / pharmacology
  • Epilepsy, Tonic-Clonic / chemically induced*
  • Epilepsy, Tonic-Clonic / physiopathology*
  • Injections, Intraventricular
  • Injections, Subcutaneous
  • Male
  • Mice
  • Morphine / pharmacology
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Quinolines / pharmacology
  • Receptors, GABA-A / physiology
  • Receptors, Opioid / physiology*
  • Receptors, Opioid, delta / physiology
  • Receptors, Opioid, kappa / physiology
  • Receptors, Opioid, mu / physiology
  • Seizures / chemically induced
  • Seizures / physiopathology
  • Synaptic Transmission / drug effects


  • Analgesics
  • Analgesics, Non-Narcotic
  • Analgesics, Opioid
  • Convulsants
  • Narcotic Antagonists
  • Quinolines
  • Receptors, GABA-A
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • TAN 67
  • Naltrexone
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • beta-funaltrexamine
  • Morphine
  • Enkephalin, D-Penicillamine (2,5)-
  • Bicuculline