SYNOPSIS Migraine headache involves the activation of trigeminal afterents that are predominantly found in the first or ophthalmic division of the nerve. The headache is often pounding and the connections of the trigeminal nerve, the trigeminovascular system, have therefore been implicated in the pathophysiology of migraine and studied extensively. Considerable attention has been given to the peripheral ramifications of the system as a possible locus of action for anti-migraine drugs while little attention has been focused upon possible central sites of action. It has been shown that certain peptides can act as markers for the trigeminal system, in particular calcitonin gene-related peptide (CGRP), and that CGRP is elevated in migraine. We have employed an animal model for activation of the trigeminovascular system to evaluate a new anti-migraine compound, 311C90, that may have central and as well as peripheral trigeminal actions. Cats were anesthetized by halothane induction and alpha-chloralose maintenance (60 mg/kg, intraperitoneal), intubated, paralyzed and ventilated. Biparietal craniotomies were carried out to measure cerebral blood flow using laser Doppler flowmetry (CBFLDF). The external jugular vein was cannulated and blood drawn, centrifuged and frozen until processing. Stimulation of the trigeminal ganglion resulted in a mean maximum increase in CBFLDF Of 39 ± 5% at 20/s. The 5HT1 agonist 311C90 was administered intravenously in two doses (30 and 100 μg/kg) to cover the range of doses likely to be effective clinically. At each dose the CBF LDF effect of trigeminal ganglion stimulation was inhibited. Stimulation of the trigeminal ganglion led to increases in both calcitonin gene-related peptide and vasoactive intestinal polypeptide (VIP) levels in the external jugular vein. These were both attenuated markedly by administration of 311C90 in a dose of 100 μg/kg. No change in either neuropeptide Y or ß-endorphin were seen during the study. These data demonstrate that trigeminal ganglion stimulation results in a brisk change in CBF LDF that can be modulated by 311C90. Furthermore the inhibition of VIP release indicates an action of the drug at the synapse in the trigeminal nucleus caudalis suggesting that this central site may have important advantages for the action of 311C90 in migraine.