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Home , Arachidonic acid

Agents Actions 38, Special Conference Issue (1993) 0065-4299/93/020C31-04 $1.50+0.20/0 rI) 1993 Birkhiiuser Verlag, Basel

Small reduction of -induced neurogenic in human forearm skin by the prednicarbate

1 Z 1 R. Tafler , M. K. Herbert\,*, R. F. Schmidt and K. H. Weis

I Institut fUr Anaesthesiologie der Universitiit Wurzburg, losef-Schneider-StraBe 2, and 2 Physiologisches Institut der Universitiit Wurzburg, Rontgenring 9, D-8700 Wurzburg, Germany

Abstract Capsaicin applied to human skin provokes a response known as neurogenic inflammation. Neuropeptides (, CGRP), released from afferent C-fiber terminals and histamine, secondarily released from mast cells, are supposed to participate in this reaction. We investigated the contribution of arachidonic acid and metabolic products to neurogenic inflammation, using a potent topically applied glucocorticoid and the corresponding vehicle. Arachidonic acid is liberated from membrane by Az, an that can be blocked by . In 12 healthy volunteers, neurogenic inflammation was induced by capsaicin 1% on both upper forearms after 16 h of topical pretreatment with either prednicarbate or vehicle. Neurogenic inflammation was assessed by laser Doppler flowmetry and by planimetry of flare sizes. Prednicarbate significantly reduced the laser Doppler flow values inside the flare responses, as well as the flare sizes themselves. These results show that to some extent glucocorticoids reduce capsaicin-induced neurogenic inflammation.

Introduction pholipids by phospholipase Az. This process is inhibited by glucocorticoids in a complex manner Capsaicin application to the skin causes vasodila­ [2]. This report is addressed to the following tation extending beyond the area of application. questions: This response is called neurogenic inflammation. It 1. What is the effect of topically applied glucocorti­ is supposed that the visible redness (flare) is due coid on capsaicin-induced neurogenic inflamma­ to axon reflex vasodilatation via primary afferent tion in human forearm skin? neurones (C-fibers), having an efferent function, i.e. 2. Does the inhibition of arachidonic acid liber­ liberating neuropeptides (e.g. substance P, CGRP) ation from membrane phospholipids influence cap­ from their terminals [I]. Besides these neuropepti­ saicin-induced neurogenic inflammation? des, other endogenous vasoactive agents have been suspected to participate in neurogenic inflamma­ Materials and methods tion. The present study was undertaken in order to assess the eventual contribution of arachidonic acid Pretreatment with prednicarbate cream and to capsaicin-induced neurogenic inflammation. vehicle cream Arachidonic acid is liberated from membrane phos- After obtaining informed consent, 12 healthy • Author for correspondence. volunteers (aged 22-31 yr) participated in this C32 Agents Actions. Special Conference Issue (1993) study, which was approved by the local ethics ness. A special holder for the LDF probe was used committee. Using a randomized schedule for the defining the positions of 12 measuring points on the choice between left and right side, 3 g prednicarbate skin: 4 measuring points inside the application area containing cream (Dermatop®, Casella Riedel) and reflecting the direct action of the substance capsai­ 3 g vehicle cream (Dermatop® Basiscreme, Casella cin plus an eventual neurogenic inflammation Riedel), respectively, were applied to square areas (inside SCBF); 8 peripheral measuring points dem­ 2 (6 x 6 cm ) on both the upper forearms. The cream onstrating the effects induced by neurogenic in­ layers were covered with occlusive dressings over­ flammation only (outside SCBF). Inside SCBF and night for 16 h. Two hours after removal of the outside SCBF were calculated as the means of the cream bandages, the skin was pretreated with respective 4 central and 8 peripheral LDF values. DMSO 10% (Merck) for 1 h to improve capsaicin In both series SCBF at rest were subtracted from absorption. the test result. All results are expressed as mean ± SO. The "Wilcoxon signed rank test" was used for statistical analyses (significance level: p < 0.05). I nduction and assessment of capsaicin-induced neurogenic injiammation Results Neurogenic inflammation was induced by 100 JlI capsaicin 1 % (Serva) soaked up in a plaster (Hansa­ SCBF following prednicarbate pretreatment and 2 plast), 13 x 18mm , applied to the skin for 25min. vehicle pretreatment were not significantly different The extent of the skin reaction to capsaicin was before capsaicin application (8.6 ± 1.2 perfusion assessed by measuring the superficial cutaneous units (p.u.); 9.9 ± 2.3 p.u.). After capsaicin applica­ blood flow (SCBF) with laser Doppler flowmetry tion, the prednicarbate pretreated side showed a (LDF) (PeriFlux PF3, PERIMED, Sweden), and by significant reduction of inside SCBF of 18% (72.0 planimetry of flare sizes, i.e. the local visible red- ± 13.3 p.u.; 62.7 ± 16.8 p.u., Fig. 1). Outside SCBF

120 INSIDE OUTSIDE SCBF SCBF

100 l- ll) u..a:W Cl VEHICLE m 80 0 en 11 PREDNICARBA TE co ::;, 60 MEAN±SD; n= 12 c 'E sig. (p

0 Figure I The effect of prednicarbate pretreatment versus vehicle pretreatment on superficial cutaneous blood flow (SeBF) of capsaicin-induced neurogenic inflammation. Inside SeBF reflects the direct effects of the capsaicin plus any additional neurogenic inflammation; outside seBF is an exclusive measure of neurogenic inflammation. Ordinate scale is in relative units of perfusion. Agents Actions, Special Conference Issue (1993) C33

3500 3000 i*l N' ! 2500 o VEHICLE cC h)t! PREONICARBA lE w 2000 a: MEAN ± SO; n = 12 cC 1500 w * sig. (p

0 Figure 2 The effect of prednicarbate pretreatment versus vehicle pretreatment on the size of capsaicin-induced flare reaction. Prednicarbate reduced the flare sizes significantly by 18%.

was also significantly reduced by 18 % following synthetase, had no effect on capsai­ prednicarbate pretreatment (59.6 ± 17.5 p.u.; 49.1 cin-induced neurogenic inflammation. The effect­ ± 19.0 p.u., Fig. 1). Further, prednicarbate reduced iveness of a glucocorticoid and the ineffectiveness of the size of flares significantly by 18% compared ASA/indomethacin indicates that arachidonic acid to vehicle (2280.1 ± 632.4 mm2; 1873.7 ± 555.0mm2, or related metabolic products other than those Fig. 2). derived from pathway may be in­ volved in the development of neurogenic inflamma­ tion. Another mode of action of the glucocorticoids Discussion could also explain our results, namely their inhibi­ The small but statistically insignificant difference tion of the expression of Ca2+ -independent NO between SCBF at rest on the corticoid pretreated synthase, assuming that the potent endogenous side versus the vehicle side is in accordance with vasodilator NO does participate in neurogenic Bisgaard et al. [3]. It has been shown that glucocor­ inflammation. This line of reasoning derives from ticoids are capable of reducing the endogenous the finding that, in contrast to constitutive Ca2 + - release of arachidonic acid by inhibition of phos­ dependent NO synthase, the expression of pholipase A2 [4]. Glucocorticoids are also sugges­ Ca2+ -independent NO synthase is inhibited by ted to inhibit the synthesis of by glucocorticoids [5]. inhibition of prostaglandin synthase enzyme ex­ pression and by coupling lipocortin to membrane phospholipids, in this way reducing the liberation References of arachidonic acid [2]. In this study, prednicarbate diminished neurogenic inflammation (flare size as [1] J. C. Foreman, The skin as an organ for the study of the well as SCBF, both significantly by 18%). In inves­ pharmacology of neuropeptides. Skin Pharmacol. 1, 77-83 (1988). tigations described elsewhere in these proceedings, [2] J. M. Bailey, New mechanisms for effects of anti-inflammatory we have shown that treatment with acetylsalicylic glucocorticoids. BioFactors 3, 97-102 (1991). acid ot indomethacin, i.e. a presumed blockade of [3] H. Bisgaard, J. K. Kristensen and J. Sondergaard, A new C34 Agents Actions, Special Conference Issue (1993)

technique for ranking vascular corticosteroid effects in humans [5] M. W. Radomski, R. M. Palmer and S. Moncada, Glucocorti­ using laser-Doppler velocimetry. J. Invest. Dermatol. 86. coids inhibit the expression of an inducible. but not the 275-278 (1986). constitutive. nitric oxide synthase in vascular endothelial cells. [4] R. Marks and M. Sawyer, Glucocorticoid-induced vasocon­ Proc. Natl. Sci. USA, 87, 10043-10047 (1990). striction in human skin. An inhibitory role on activity. Arch. Dermatol. 122. 881-883 (1986).