Neuronal PAC1receptors mediate delayed activation and sensitization of trigeminocervical neurons: Relevance to migraine

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.