Despite the high prevalence of migraine in the general population, our understanding of the underlying mechanisms remains incomplete. A variety of theories focused on peripheral neural or neurovascular mechanisms have been put forward, but none of these has so far received conclusive experimental support. An alternative proposal is that migraine is triggered, or at least maintained, by a "central generator" in the brain itself. We recently showed that the rostral ventromedial medulla (RVM), a region with a well documented role in pain modulation, contributes to behavioral hypersensitivity following dural inflammation, an animal model of migraine headache. The proposed studies will test the role of specific population of RVM neurons, termed "ON-cells", in this model. To accomplish this, we will record activity of identified RVM painmodulating neurons before and after dural inflammation and determine whether ON-cell mediate observed behavioral changes by manipulating the activity of this and other RVM cell classes using pharmacological tools. The experiments described in this proposal will attempt to delineate a more complete theory of migraine headache pain by extending the idea of "central sensitization" in migraine headache to brainstem modulatory systems. We expect to find important support for the idea of a "central generator" in migraine headache pain. This idea is attractive because a central dysfunction could potentially explain the multiple triggers for migraine attached, as well as the range of associated symptoms, including nausea and aversion to light and sound.