S+ -flurbiprofen but not 5-HT1 agonists suppress basal and stimulated CGRP and PGE2 release from isolated rat dura mater.
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.
Zimmermann
K
K
Institute of Physiology and Experimental Pathophysiology, University of Erlangen-Nürnberg, Universitätsstr. 17, D-91054 Erlangen, Germany.
Reeh
W P
WP
Averbeck
B
B
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
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