The pathophysiological basis for the
pain of
migraine has been the subject of substantial attention and must include activation of elements of the trigeminal innervation of the cranial vessels, the trigeminovascular system. Recently, consideration of trigeminal-evoked neurogenic
plasma protein extravasation (PPE) as a model for the
pain has driven the search for compounds with specific anti-extravasation properties.
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 but does not itself produce PPE. It has been suggested that 5HT(1B/1D)agonists may have an anti-
migraine effect via inhibition of PPE in the dura mater.
Avitriptan and CP122,288 both have strong binding affinities for 5HT(1B/1D)receptors, but only CP122,288 is a potent inhibitor of PPE. In this study we sought to compare the effects of CP122,288 and
avitriptan on jugular vein CGRP release after stimulation of the superior sagittal sinus (SSS) in the cat. In eleven anaesthetized cats external jugular vein blood samples were analyzed by radioimmunoassay for CGRP levels in three settings: a) control, b) 1 min after SSS stimulation and c) 1 min after SSS stimulation in presence of
drug. Stimulation of the SSS resulted in release of CGRP from the external jugular vein (77+/-1 pmol/L). At a PPE-inhibitory dose in rat (100 ng/kg intravenously) CP122, 288 had no effect on CGRP release (77+/-6 pmol/L) whereas at a clinically relevant dose (50 microgram/kg intravenously)
avitriptan blocked CGRP release. This study demonstrates that the potent inhibitor of PPE, CP122, 288, which has been shown in clinical trials to be ineffective in treating acute
migraine attacks, had no effect on CGRP release, whereas the effective anti-
migraine drug and relatively impotent inhibitor of PPE,
avitriptan, blocked CGRP release. These data emphasize the importance of CGRP release and its possible independence from PPE in
migraine and more importantly suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.