Their investigation showed that repeated intranasal PACAP treatments caused mechanical and thermal hyperalgesia like NTG injections. The impact of PACAP on migraine attacks involves PAC1 receptor internalization and PKA and ERK signaling pathways. This is the first research to show that inhibiting PACAP-induced PAC1 receptor internalization improves hyperalgesia in CM rats by restricting ERK signaling. PACAP-induced trigeminal vascular activation requires further study to determine the process and uncover additional targets that modulate PAC1 receptor internalization with specificity. This evidence concerns the gene ADCYAP1R1 and migraine disorder.