A delayed endothelial-glial mechanism for CGRP-induced migraine.

CGRP plays a crucial role in migraine and trigeminovascular signaling. However, how CGRP causes delayed migraine-like pain after infusion is unclear. Although evidence supports CGRP’s role, the exact mechanisms remain unknown. We propose a hypothesis where CGRP triggers a delayed signaling cascade. This cascade sensitizes trigeminal afferents over time. CGRP not only promotes arterial vasodilatation but also activates glial responses. These responses involve transcription-dependent processes and ion channel modulation. This process can evolve over hours, explaining delayed migraine onset. Peripheral endothelial-glial signaling may amplify at ganglionic and spinal levels. This amplification contributes to sensitization in trigeminovascular pathways. During spontaneous migraine attacks, CGRP release results from primary afferent excitation. This excitation occurs through excess nitric oxide activating transient receptor potential channels. Most likely, this is initiated by endothelial dysfunction from metabolic disturbances. Our model integrates CGRP biology, delayed migraine induction, and glial signaling for better understanding. Clinical relevance: This research suggests that targeting CGRP and glial signaling may improve migraine treatments.