Strong evidence supports the idea that NO plays a pivotal role in the pathogenesis of migraine [27, 28], a disorder characterized by pain sensitization associated with cranial vascular changes [29–31], but mechanisms and modalities of NO activity are still largely unknown. Systemic GTN activates neuronal groups in selected areas of the rat brain involved in nociception [21, 32, 33] and induces spontaneous-like attacks in migraineurs via multimodal mechanisms that include GTN- induced vasodilation, peripheral sensitization induced by the increased availability of NO at the trigeminovascular level, and possibly also central sensitization [34–37].