title: S+ -flurbiprofen but not 5-HT1 agonists suppress basal and stimulated CGRP and PGE2 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-HT1) 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.
authors.affiliation: Institute of Physiology and Experimental Pathophysiology, University of Erlangen-Nürnberg, Universitätsstr. 17, D-91054 Erlangen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Zimmermann
authors.forename: W P
authors.initials: WP
authors.lastname: Reeh
authors.forename: B
authors.initials: B
authors.lastname: Averbeck
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004347:Drug Interactions; D004388:Dura Mater / Q000187:drug effects* / Q000378:metabolism; D005480:Flurbiprofen / Q000494:pharmacology*; D007118:Immunoassay / Q000379:methods; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013997:Time Factors; D014363:Tryptamines
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017077:Culture Media, Conditioned; D007211:Indoles; D018836:Inflammation Mediators; D010880:Piperidines; D011725:Pyridines; D011758:Pyrroles; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one; D005480:Flurbiprofen; D015740:Calcitonin Gene-Related Peptide; D015232:Dinoprostone; C106783:naratriptan