Anticonvulsant and neuroprotective actions of endogenous dynorphin

Anticonvulsant actions of dynorphin were proposed since more than 2 decades, however till now, we do not have information on the functions of endogenous dynorphin. Thus, we investigated prodynorphin knockout (KO) mice in different models of seizures and epilepsy. Seizure threshold was investigated by tail-vein infusion of 100 μg pentylenetetrazole (PTZ)/ml at a rate of 100 μl/min until mice displayed generalized clonic seizures. Wild-type mice showed clonic seizures at 39.2 ± 1.88 (mean ± SEM; n = 5) mg PTZ/kg body weight. KOs displayed a significantly reduced seizure threshold of 32.7 ± 1.17 (n = 6) mg PTZ/kg. This phenotype could be rescued entirely by the κ opioid receptor specific agonist U-50488, but not the μ opioid receptor specific agonist DAMGO. The δ opioid receptor specific agonist SNC80 decreased seizure threshold in both genotypes. Pre-treatment with the κ-selective antagonist GNTI completely blocked the rescue effect of U-50488. After injection of kainic acid into stratum radiatum of CA1 of the dorsal hippocampus, KO mice displayed increased neuronal loss along the rostro-caudal axis of the ipsi- and partially the contralateral hippocampus at early time points after treatment. Thus, marked neurodegeneration was seen already 1 week after treatment in KO mice. The differences faded with time, being almost gone 5 weeks after kainate. Our data clearly indicate that endogenous prodynorphin derived peptides have anticonvulsant and neuroprotective properties.