We tested the idea that migraine triggers cause cortical activation, which disinhibits craniovascular sensation through the nucleus raphe magnus (NRM) and thus produces the headache of migraine. Stimulation of the dura mater and facial skin activated neurons in the NRM and the trigeminal nucleus. Stimulation of the NRM caused suppression of responses of trigeminal neurons to electrical and mechanical stimulation of the dura mater, but not of the skin. This suppression was antagonized by the iontophoretic application of the 5-HT1B/1D receptor antagonist GR127935 to trigeminal neurons. Migraine trigger factors were simulated by cortical spreading depression (CSD) and light flash. Activity of neurons in the NRM was inhibited by these stimuli. Multiple waves of CSD antagonized the inhibitory effect of NRM stimulation on responses of trigeminal neurons to dural mechanical stimulation but not to skin mechanical stimulation. The cortico-NRM-trigeminal neuraxis might provide a target for a more universally effective migraine prophylactic treatment.