The major drugs used to treat migraine in the 19th and 20th century (ergot alkaloids, triptans) were found by Moskowitz and colleagues[7][6] to inhibit neuropeptide release from TV axons as their major mechanism of action.
Because drugs that block the release of neuropeptides from trigeminovascular fibres are therapeutically relevant for relieving migraine headaches (especially CGRP to date), hence, it has been hypothesized that the trigeminovascular system may be involved in migraine headaches.
[3][8][9] Studies of the TVS have helped to identify therapeutic targets for migraine including onabotulinum toxin, 5-HT1F receptor agonist (lasmiditan),5-HT1B,D[10] as well as CGRP and its receptor system[11] including both small molecule drugs and biologicals.
Numerous experimental studies have established that cortical spreading depolarization, the biological substrate for migraine aura, can discharge trigeminovascular afferents as a cause of head pain and by extension unilateral headache overlying the dysfunctional hemisphere in migraineurs with aura.
[12] Hence, the TVS has provided a template for migraine pathophysiology and target for drug discovery.