Research ArticleMigraine

Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: Relevance to migraine

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Science Translational Medicine  07 Oct 2015:
Vol. 7, Issue 308, pp. 308ra157
DOI: 10.1126/scitranslmed.aaa7557

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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. now 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. The authors therefore compared the abilities of these peptides to induce an increase in the ongoing spontaneous firing of central trigeminovascular neurons and found that PACAP-38, but not VIP, was effective. 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, were able to mediate dural-nociceptive trigeminocervical neurons. Thus, migraine is likely to be triggered via PACAP-38 acting on PAC1 receptors within the brain.


The pathogenesis of migraine is not well understood. To dissect the relative contributions of endogenous peripheral and central mechanisms in triggering migraine, we examined the effects of two pharmacologically similar, but clinically different, vasodilator neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide 38 (PACAP-38), on dural meningeal vessels and the response properties of central trigeminovascular neurons. Both VIP and PACAP-38 caused short-lived meningeal vasodilation mediated by VPAC2 receptors, which did not coincide with activation of central trigeminovascular neurons. Only PACAP-38 caused delayed activation and sensitization of central trigeminovascular neurons, similar to its delayed effects in inducing migraine headache. After a 90-min delay, PACAP-38 induced a robust increase in ongoing spontaneous firing and hypersensitivity to intra- and extracranial somatosensory stimulation, which did not coincide with meningeal vasodilation. Only intravenous delivery of a PAC1 receptor antagonist inhibited the peripheral meningeal vasodilatory effects of dural trigeminovascular nociception, whereas only central (intracerebroventricular) administration of the PAC1 receptor antagonist inhibited dural nociceptive–evoked action potentials in central trigeminovascular neurons. Our data suggest that the endogenous mechanisms of migraine pathogenesis are located within the central nervous system, likely in the trigeminocervical complex, and that the dural meninges and their primary afferent innervation are less likely to contribute to migraine initiation. Furthermore, the PAC1 receptor may be an appropriate molecular target for migraine therapeutics.

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