The development of serotonin (5HT1B/1D) agonists as treatments for the acute of migraine has resulted in considerable interest in their mechanism of action and, to some extent, renewed interest in the role of serotonin (5-hydroxytrypatmine; 5HT) in the disorder. The initial synthesis of this class of compounds was predicated on the clinical observation that intravenous 5HT terminated acute attacks of migraine. In this study the superior sagittal sinus was isolated in the α-chloralose (60mg/kg IP and 20 mg/kg IV injection supplementary 2 hourly) anesthetized cat. The sinus was stimulated electrically (120V, 250 °sec duration, 0.3 Hz), and neurons of the trigeminocervical complex in the dorsal C2 spinal cord were monitored using electrophysiological methods. After baseline recordings in each animal, 5HT (15 μg/kg/min) was infused for 5 minutes in the presence of either vehicle (group A) or the 5HT 1B/1D antagonist GR127935 (100 μg/kg IV injection; group B). The baseline probability of cell firing after sagittal sinus stimulation was 0.61 ± 0.1 at a latency to the fastest peak of 11.1 ± 0.4 msec. In group A, 5HT infusion alone had a small effect of increasing mean blood pressure (12 ± 3 mm Hg), which in itself did not alter cell firing. In group A, 5HT alone had an inhibitory effect on evoked trigeminal activity, which developed 15 to 20 minutes after commencement of the infusion. The inhibition of cell firing lasted for 20 minutes, after which the activity returned to baseline. In group B, the combination of 5HT and GRI127935 had no effect on trigeminal cell firing, although the small hypertensive effect was still present. These data indicate that 5HT inhibits evoked trigeminal nucleus firing via the 5HT 1B/1D receptor at which GRI127935 is an antagonist. It is likely that some part of the effect of 5HT in migraine relates to inhibition of trigeminal nucleus activity, just as it is likely that some part of the effect of the triptans is also mediated at this central site and may be complementary to their nonneuronal actions. Moreover, the data highlight the case for describing this class of headache as neurovascular headaches rather than vascular headaches, to recognize the implicit contribution of the trigeminovascular system to their pathophysiology.