Inflammatory mediators do not stimulate CGRP release if prostaglandin synthesis is blocked by S(+)-flurbiprofen in isolated rat skin.
OBJECTIVE
Nonsteroidal antiinflammatory drugs are well known as antipyretic analgesics, however, their mode of action is not yet fully understood. Besides their cyclooxygenase (COX) blocking effect other action principles are discussed. In the present study we investigated the effects of the flurbiprofen enantiomers on the stimulated release of calcitonin gene-related peptide (CGRP) from the isolated rat skin as an indirect measure of peripheral nociceptor activation and 'neurogenic inflammation'.


METHODS
Stimulation was performed by a combination of inflammatory mediators (bradykinin, serotonin and histamine, all 10(-5) M). In addition, prostaglandin E(2) (PGE(2)) release was determined in order to verify the inhibitory effect of the tested drugs on prostaglandin production.


RESULTS
S(+)-flurbiprofen (10(-7) and 10(-6) M), reported as the COX blocking enantiomer, completely blocked basal as well as stimulated PGE(2) release. Under R(-)-flurbiprofen a reduction of basal PGE(2) release was not significant; the stimulated PGE(2) release, was however significantly reduced at 10(-7) M and completely suppressed at 10(-6) M drug concentration. The stimulated CGRP release was not affected by R(-)-flurbiprofen (10(-7) or 10(-6) M). In contrast, S(+)-flurbiprofen - only at 10(-6) M - significantly reduced the inflammatory mediator-induced CGRP release. This reduction could be reversed by co-administration of PGE(2) (10(-5) M) suggesting that the effect was due to COX block and prostanoid deprivation.


CONCLUSIONS
Although a higher concentration of the effective enantiomer was needed to inhibit stimulated CGRP than PGE(2) release, flurbiprofen seems to exert the antinociceptive/antiinflammatory effects observed by preventing the secondary cutaneous prostaglandin formation that appears necessary to enable activation by inflammatory mediators of the CGRP-releasing nerve fibers.
Aventis Pharma Deutschland GmbH, Industriepark Höchst, Building H821, 65926 Frankfurt, Germany.
B
B
Averbeck
M
M
Peisler
I
I
Izydorczyk
P W
PW
Reeh
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis* / Q000378:metabolism; D005480:Flurbiprofen / Q000494:pharmacology*; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000494:pharmacology*; D008297:Male; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D012701:Serotonin; D005480:Flurbiprofen; D011189:Potassium Chloride; D006632:Histamine; D015740:Calcitonin Gene-Related Peptide; D015232:Dinoprostone; D001920:Bradykinin