Our results suggest that PACAP38-MrgprB2 could cause stress-induced headache behaviour via TNF-α and TRPV1 and highlight the the possibility that the PACAP38-MrgprB2 axis is a key mediator of stress-induced migraine, a promising avenue for the development of migraine treatments beyond CGRP-based therapies. Here, TRPV1 is linked to Headache.