This suggests that the possible bi-directional relationship between trigeminal meningeal nociceptors and MCs could be capable of evoking the release of a plethora of migraine-inducing mediators which may induce the onset or intensification of migraine.31,32,42,47 This prompts the hypothetical mechanism whereby trigeminal nerve stimulation results in the release of neuropeptides CGRP and PACAP-38 from trigeminal meningeal nociceptors, which are compounds understood to be capable of evoking the degranulation of MCs (Figure 2). This evidence concerns the gene ADCYAP1 and migraine disorder.