Epilepsy remains a major medical problem of unknown aetiology. Potentially, viruses can be environmental triggers for development of seizures in genetically vulnerable individuals. An estimated half of encephalitis patients experience seizures and approximately 4% develop status epilepticus. Epilepsy vulnerability has been associated with a dynorphin promoter region polymorphism or low dynorphin expression genotype, in man. In animals, the dynorphin system in the hippocampus is known to regulate excitability. The present study was designed to test the hypothesis that reduced dynorphin expression in the dentate gyrus of hippocampus due to periadolescent virus exposure leads to epileptic responses. Encephalitis produced by the neurotropic Borna disease virus in the rat caused epileptic responses and dynorphin to disappear via dentate granule cell loss, failed neurogenesis and poor survival of new neurons. Kappa opioid (dynorphin) agonists prevented the behavioural and electroencephalographic seizures produced by convulsant compounds, and these effects were associated with an absence of dynorphin from the dentate gyrus granule cell layer and upregulation of enkephalin in CA1 interneurons, thus reproducing a neurochemical marker of epilepsy, namely low dynorphin tone. A key role for kappa opioids in anticonvulsant protection provides a framework for exploration of viral and other insults that increase seizure vulnerability and may provide insights into potential interventions for treatment of epilepsy.