Cortical spreading depression (SD) is thought to underlie the migraine aura but the mechanisms of triggering SD in the human cortex remain unknown. Because growing evidence points to a key role of brainstem circuits in initiating migraine attacks, the present study examined whether recurrent episodes of brainstem activation in rats could induce cortical SD. Explosive running elicited by sounds in rodents with inherited hypersensitivity to acoustic stimuli (reflex audiogenic epilepsy), is known to reflect a transient aberrant activation of the brainstem. Repeated induction of such audiogenic responses enhances the excitability of the cortex, culminating in its epileptic activation (audiogenic kindling). In Wistar rats with inherited hypersensitivity to sounds, 15 brief episodes of running were induced by sound stimulation, and slow potential shifts as well as the EEG were recorded in the cortex. Single unilateral SD began to occur in the cortex following a running episode after the 5th to 15th test (mean 9.4+/-1.2). Once appeared, SD was regularly recorded in subsequent tests. The side of the SD initiation closely correlated with the direction of running. Triggering SD was not associated with epileptic activation of the cortex in most rats. The present findings suggest that the sensory-induced brainstem excitation could be a potent trigger of SD in the hyperexcitable cortex, providing an experimental evidence of a possible causative role of the brainstem activation in initiating the migraine aura.