S(+)-flurbiprofen but not 5-HT 1 agonists suppress basal and stimulated CGRP and PGE 2 release from isolated rat dura mater

Abstract

Neurogenic inflammation of the meninges, expressed in plasma extravasation and vasodilatation, putatively contributes to certain types of headache. Both, non-steroidal antiinflammatory drugs (NSAIDs) and serotonin-1 (5-HT 1) receptor agonists are similarly effective antimigraine drugs but their mechanism of action is unclear. The clinical observation that sumatriptan lowered plasma levels of calcitonin gene-related peptide (CGRP), found increased during migraine attacks, drew attention to a possible inhibition of pro-inflammatory neuropeptide release from trigeminal afferents. An isolated preparation of fluid-filled rat skull cavities was used to study effects of NSAIDs and 5-HT 1B/D agonists on the dura stimulated by inflammatory mediators (bradykinin, histamine and serotonin, 10 −5 M each). The release of immunoreactive CGRP (iCGRP) and immunoreactive PGE 2 (iPGE 2) was measured in 5-min samples of superfusates using enzyme immunoassays. S(+)-flurbiprofen (10 −6 M) strongly reduced the basal and stimulated iCGRP release and abolished iPGE 2 release; R(−)-flurbiprofen showed much less effect on iPGE 2 liberation and did not influence iCGRP release. The 5-HT 1B/D agonists naratriptan and CP93,129 were ineffective on both iCGRP and iPGE 2 release. Inspite of its weak COX blocking effect, R(−)-flurbiprofen is reported to exert antinociceptive effects, although it has not been tested in migraine. Only the potent COX blocker S(+)-flurbiprofen also suppressed iCGRP release while the 5-HT 1B/D agonists were ineffective. Thus, inhibition of meningeal neuropeptide secretion is not a common action principle of the drugs that could be essential for their antimigraine effects.