Selective Inhibition of 5-HT7 Receptor Reduces CGRP Release in an Experimental Model for Migraine

Objective.- To investigate the role of 5-HT7 receptors on the release of calcitonin gene-related peptide (CGRP) in an animal model of migraine. Background.- Calcitonin gene-related peptide has been identified as a key neuropeptide in the pathophysiology of migraine. It is elevated in the external jugular vein during migraine attacks in humans and after stimulation of the trigeminal ganglion in animal models of migraine. This can be treated with the 5-HT1B/1D receptor agonist sumatriptan concomitant with headache relief. Nevertheless, triptans, the most effective agents for the treatment of acute migraine attacks, are not effective in more than 1/3 of migraineurs and less than 50% of migraineurs achieve complete pain freedom. This indicates other serotonin receptors may be involved in the pathophysiology of migraine. Increasing evidence has shown that 5-HT7 receptors may be involved in migraine pathogenesis. However, direct evidence for the role of 5-HT7 receptors in migraine is still lacking. Methods.- Unilateral electrical stimulation of the trigeminal ganglion (TGES) was performed in anesthetized male Sprague-Dawley rats. Animals were pretreated with sumatriptan (300 mu g/kg, i.v.), selective 5-HT7 receptor antagonist SB269970 (5, 10 mg/kg, s.c.), potential 5-HT7 receptor agonist AS19 (5, 10 mg/kg, s.c.) or co-administration of SB269970 and AS19 (10 mg/kg, s.c.). Serum CGRP concentrations in the ipsilateral jugular vein were determined before and at 2 and 5 minutes after the start of TGES. Results.- Our results showed that sumatriptan almost completely inhibited the release of CGRP evoked by TGES. Pre-administration of SB269970 (5, 10 mg/kg) caused a significant decrease in serum CGRP concentrations at 2 and 5 minutes following the onset of TGES, with a less inhibitory effect compared with sumatriptan. AS19 had no significant effect on CGRP release, while the SB269970-induced inhibitory effect was reversed by AS19. Conclusions.- Selective inhibition of 5-HT7 receptors partly reduced CGRP release evoked by TGES. These findings suggest that 5-HT7 receptors may play a role in the pathophysiology of migraine. (Headache 2010;50:579-587).