Neuropsychiatric disorders are one of the main challenges of human medicine with
epilepsy being one of the most common serious disorders of the brain. Increasing evidence suggest
neuropeptides, particularly the
opioids, play an important role in
epilepsy. However, little is known about the mechanisms of the endogenous
opioid system in epileptogenesis and
epilepsy. Therefore, we investigated the role of endogenous
prodynorphin-derived
peptides in epileptogenesis, acute seizure behaviour and
epilepsy in
prodynorphin-deficient mice. Compared with wild-type littermates,
prodynorphin knockout mice displayed a significantly reduced seizure threshold as assessed by tail-vein infusion of the
GABA(A) antagonist
pentylenetetrazole. This phenotype could be entirely rescued by the
kappa receptor-specific agonist
U-50488, but not by the
mu receptor-specific agonist
DAMGO. The delta-specific agonist
SNC80 decreased seizure threshold in both genotypes, wild-type and knockout. Pre-treatment with the kappa selective antagonist GNTI completely blocked the rescue effect of
U-50488. Consistent with the reduced seizure threshold,
prodynorphin knockout mice showed faster seizure onset and a prolonged time of seizure activity after intracisternal injection of
kainic acid. Three weeks after local injection of
kainic acid into the stratum radiatum CA1 of the dorsal hippocampus,
prodynorphin knockout mice displayed an increased extent of granule cell layer dispersion and neuronal loss along the rostrocaudal axis of the ipsi- and partially also of the contralateral hippocampus. In the classical
pentylenetetrazole kindling model,
dynorphin-deficient mice showed significantly faster kindling progression with six out of eight animals displaying
clonic seizures, while none of the nine wild-types exceeded rating 3 (forelimb clonus). Taken together, our data strongly support a critical role for
dynorphin in the regulation of hippocampal excitability, indicating an
anticonvulsant role of
kappa opioid receptors, thereby providing a potential target for
antiepileptic drugs.