The pain is mostly in the brain

More than just a throbbing headache, migraines also cause hypersensitivity to light and sound, nausea and vomiting, and other sensory disturbances. Exactly what goes wrong during these episodes of excruciating pain is not completely clear, and it is debated whether the salient mechanism is a peripheral or central (with the central nervous system) phenomenon. Akerman et al. provide evidence from rats that migraine is triggered by central effects on trigeminocervical neurons and identify a therapeutic target, PAC1 receptors. Of two similar vasodilator neuropeptides, VIP and PACAP-38, only PACAP-38 causes migraine in patients. PACAP-38, but not VIP, increased the spontaneous firing of central trigeminovascular neurons. PACAP-38 also enhanced responses to sensory stimulation, but this was independent of any peripheral changes. Of the PACAP-type receptors, only the centrally located PAC1 receptors mediated dural-nociceptive trigeminocervical neurons. Thus, migraine may be triggered by PACAP-38 acting on PAC1 receptors within the brain. S. Akerman, P. J. Goadsby, Neuronal PAC 1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: Relevance to migraine. Sci. Transl. Med. 7 , 308ra157 (2015). [Abstract]