| Summary: | Migraine headache is one of the most common neurological disorders. While the mechanisms contributing to migraine pathophysiology have yet to be fully elucidated, the disproportionate number of post-pubescent, pre-menopausal women affected suggests a central role for female hormones, such as estrogen. The mechanism(s), however, by which estrogen contributes to migraine have yet to be deciphered. Cortical spreading depression (CSD) is associated with "Classic Migraine", now referred to as migraine with aura. Here we use a well-established animal model for migraine with aura to test the putative role of estrogen in the development of CSDs in awake and freely moving female rats. Beta estradiol administration in ovariectomized female rats resulted in a significant increase in CSD episodes over a 12-hour recording period. Additionally, beta estradiol administration in these rats promoted migraine-associated behavior, significantly reducing exploratory behavior (i.e., number of vertical rearing episodes) when compared to vehicle-treated controls. Critically, the increase in CSD episodes was completely abolished with pre-administration of ICI 182,780 a pure alpha and beta estrogen receptor antagonist. ICI 182,780administration also blocked beta estradiol-induced migraine-associated behaviors, restoring vertical rearing episodes to baseline levels. These data illustrate that an increase in estrogen levels in an animal that no longer produces estrogen (postmenopausal characteristic) can promote the development of CSDs. These data suggest that an estrogen receptor-mediated mechanism may drive episodes of migraine with aura and highlight the need for further investigation into estrogen's role in migraine.
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