Spontaneous Cortical Spreading Depressions in Freely-Moving Rats: Implications for their Role in the Pathophysiology of Migraine

Abstract

Migraine is a prevalent and potentially debilitating neurological disorder with complex pathophysiology. Previous studies have provided compelling evidence for a role of Cortical Spreading Depression (CSD) in the symptomatology of migraine, most importantly the auras experienced by a subset of migraineurs. However, the precise role of CSD in the development of other symptoms of migraine, most notably pain, is less certain. Limitations of previous animal models of CSD have proven problematic in our ability to elucidate the role of these events in the development of migraine pain. In the newly developed animal model described here, electrical activity was recorded from multiple sites on the cerebral cortex in freely-moving animals. This model allows for recording bioelectrical changes in the cortex while concurrent behavioral changes are being measured. In contrast to other studies that employ invasive measures to evoke CSD, recordings described here are from animals that have not undergone any cortical insult, but alternatively received prolonged treatment with sumatriptan, an agent demonstrated to contribute to the development of medication-overuse headache when administered chronically. The studies described here show that animals pretreated with sustained sumatriptan have a significant increase in frequency of spontaneous CSDs. Moreover, this increase in frequency is augmented following exposure of animals to a bright light stress. These findings demonstrate a lowered threshold of cerebral cortex for development of spreading depression. These findings also suggest a dissociation between development of CSD and activation of nociceptive pathways responsible for migraine headache. Additionally, these findings show that this is a viable platform for further study of CSD in freely-moving animals and their function in the development of migraine headache. The implications of these findings on the understanding of the role of CSD in migraine headache pathogenesis are significant.