Cyclo-oxygenase and lipoxygenase pathways in mast cell dependent-neurogenic inflammation induced by electrical stimulation of the rat saphenous nerve

1 We investigated the role of arachidonic acid metabolism and assessed the participation of mast cells and leukocytes in neurogenic inflammation in ra t paw skin. We compared the effect of lipoxygenase (LOX) and cyclo-oxygenas e (COX) inhibitors on oedema induced by saphenous nerve stimulation, substa nce P (SP), and compound 48/80. 2 Intravenous (i.v.) pre-treatment with a dual COX/LOX inhibitor (RWJ 63556 ), a dual LOX inhibitor/cysteinyl-leukotriene (CysLt) receptor antagonist ( Rev 5901), a LOX inhibitor (AA 861), a five-lipoxygenase activating factor (FLAP) inhibitor (MK 886), or a glutathione S-transferase inhibitor (ethacr ynic acid) significantly inhibited (40 to 60 %) the development of neurogen ic oedema, but did not affect cutaneous blood flow. Intradermal (i.d.) inje ction of LOX inhibitors reduced SP-induced oedema (up to 50% for RWJ 63556 and MK 886), whereas ethacrynic acid had a potentiating effect. 3 Indomethacin and rofecoxib, a highly selective COX-2 inhibitor, did not a ffect neurogenic and SP-induced oedema. Surprisingly, the structurally rela ted COX-2 inhibitors, NS 398 and nimesulide, significantly reduced both neu rogenic and SP-induced oedema (70% and 42% for neurogenic oedema, respectiv ely; 49% and 46% for SP-induced oedema, respectively). 4 COX-2 mRNA was undetectable in saphenous nerves and paw skin biopsy sampl es, before and after saphenous nerve stimulation. 5 A mast cell stabilizer, cromolyn, and a H-1 receptor antagonist, mepyrami ne, significantly inhibited neurogenic (51% and 43%, respectively) and SP-i nduced oedema (67% and 63%, respectively). 6 The co-injection of LOX inhibitors and compound 48/80 did not alter the e ffects of compound 48/80. Conversely, ethacrynic acid had a significant pot entiating effect. The pharmacological profile of the effect of COX inhibito rs on compound 48/80-induced oedema was similar to that of neurogenic and S P-induced oedema. 7 The polysaccharide, fucoidan (an inhibitor of leukocyte rolling) did not affect neurogenic or SP-induced oedema. 8 Thus, (i) SP-induced leukotriene synthesis is involved in the development of neurogenic oedema in rat paw skin; (ii) this leukotriene-mediated plasm a extravasation might be independent of mast cell activation and/or of the adhesion of leukocytes to the endothelium; (iii) COX did not appear to play a significant role in this process.