As more small peptidergic components of the central nervous system are isolated, their role in disease states is being investigated. Several of these neuropeptides, especially the opioidlike peptides, adrenocorticotropic hormone, and some hypothalamic releasing factors, have been found to alter neuronal excitability. This finding has led to the proposal that these peptides may play a role in the pathogenesis of the epilepsies. We tested this hypothesis in a genetic model of epilepsy. At nontoxic doses, several exogenously administered peptides had anticonvulsant properties, while others were proconvulsant. The most potent anticonvulsant was the opioidlike peptide beta-endorphin. Its effect was similar to that of the opioid alkaloids. Using the potent antagonist naloxone hydrochloride to block possible endogenous opioid-like peptides, we found no effects on seizures in naive animals. Naloxone did alter postictal events, however, by partially blocking the postictal refractoriness to further seizures. We speculate that one possible role for the endogenous opioid peptides may be to limit the spread of seizures or to modulate postictal susceptibility to further seizures. Naloxone was effective in this model only after stressful situations occurred that modified the seizures and presumably induced a release of endogenous opioidlike peptides. Support for this hypothesis from other epilepsy models is discussed. Other peptidergic systems may also be active in various epileptic models, and the current understanding of their roles is reviewed.