Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. CGRP may have a role in migraine through its potent cranial vasodilator effects, or by an action on trigeminal nerve activity, both of which are targeted by 5HT(1B/1D) agonist drugs. CP122,288, a conformationally restricted analogue of sumatriptan that is a potent inhibitor of neurogenic plasma protein extravasation (PPE), was ineffective at inhibiting CGRP release at a single low dose; and is also ineffective as an acute anti-migraine compound. However, it remained unclear as to whether, as a class, the conformationally-restricted triptan analogues could have inhibitory effects on CGRP in higher doses. 4991W93, a conformationally restricted analogue of zolmitriptan, is also a potent inhibitor of PPE at doses without 5HT(1B/1D)-mediated effects, that was developed as an anti-migraine drug, and thus was suitable to test whether higher doses of such conformationally restricted triptan analogues could inhibit trigeminal-evoked CGRP release. The superior sagittal sinus (SSS) was stimulated in 14 anaesthetised cats and external jugular vein blood samples were analysed by radioimmunoassay for CGRP levels before, 1 min after SSS stimulation, and 1 min after SSS stimulation in the presence of 4991W93. Stimulation of the SSS resulted in release of CGRP from the external jugular vein. 4991W93 at a dose of 0.1 and 10 microg/kg, selected for maximal PPE blocking effects in rodents, was ineffective at inhibiting CGRP release, with an SSS stimulation level of 78+/-4 pmol/l compared to a post-4991W93 level of 79+/-3 pmol/l (n=4). In comparison CGRP release was inhibited after a dose of 100 microg/kg 4991W93 from 64+/-6 to 36+/-3 pmol/l (n=5). Given that 4991W93 is inactive clinically at non-vascular doses, it seems clear that the 5HT(1B/1D) agonist effects of the compound are necessary for blockade of CGRP release and thus any anti-migraine action. Taken with the clinical results, these data emphasise the importance of CGRP release in migraine, and suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.