Inflammatory mediators do not stimulate CGRP release if prostaglandin synthesis is blocked by S(+)-flurbiprofen in isolated rat skin
Inflammatory mediators do not stimulate CGRP release if prostaglandin synthesis is blocked by S(+)-flurbiprofen in isolated rat skin
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DOI：
10.1007/s00011-003-1209-1
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发表时间：
2003-12-01
影响因子：
6.7
通讯作者：
Reeh, PW
中科院分区：
文献类型：
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作者：
Averbeck, B;Peisler, M;Reeh, PW
目的：非甾体类解热镇痛药是众所周知的解热镇痛药，但其作用机制尚不完全清楚。除了对环氧合酶（考克斯）的阻断作用外，还讨论了它们的其他作用机理。在本研究中，我们研究了氟比洛芬对映体对降钙素基因相关肽（CGRP）从离体大鼠皮肤刺激释放的影响，作为外周伤害感受器激活和“神经源性炎症”的间接测量方法：刺激由炎症介质（缓激肽，血清素和组胺，所有10（-5）M）的组合进行。结果：S（+）-氟比洛芬（10（-7）M和10（-6）M），作为考克斯阻断剂，完全阻断基础和刺激的PGE（2）释放。在R（-）-氟比洛芬作用下，基础PGE（2）释放的减少不显著;然而，刺激的PGE（2）释放在10（-7）M药物浓度下显著减少，在10（-6）M药物浓度下完全抑制。R（-）-氟比洛芬（10（-7）或10（-6）M）不影响CGRP的释放。相比之下，S（+）-氟比洛芬-仅在10（-6）M -显着减少炎症介质诱导的CGRP释放。这种减少可以通过共同给予PGE（2）（10（-5）M）来逆转，这表明该作用是由于考克斯阻断和前列腺素剥夺。尽管抑制刺激的CGRP释放需要比PGE（2）更高浓度的有效对映体，氟比洛芬似乎发挥抗伤害性/通过防止继发性皮肤前列腺素形成观察到抗炎作用，这种前列腺素形成似乎是炎症介质激活CGRP释放神经纤维所必需的。
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.Conclusion: 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.