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

Abstract

1 We investigated the role of arachidonic acid metabolism and assessed the participation of mast cells and leukocytes in neurogenic in¯ammation in rat paw skin. We compared the eect of lipoxygenase (LOX) and cyclo-oxygenase (COX) inhibitors on oedema induced by saphenous nerve stimulation, substance 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 ®ve-lipoxygenase activating factor (FLAP) inhibitor (MK 886), or a glutathione S-transferase inhibitor (ethacrynic acid) signi®cantly inhibited (40 to 60%) the development of neurogenic oedema, but did not aect cutaneous blood¯ow. Intradermal (i.d.) injection of LOX inhibitors reduced SP-induced oedema (up to 50% for RWJ 63556 and MK 886), whereas ethacrynic acid had a potentiating eect. 3 Indomethacin and rofecoxib, a highly selective COX-2 inhibitor, did not aect neurogenic and SP-induced oedema. Surprisingly, the structurally related COX-2 inhibitors, NS 398 and nimesulide, signi®cantly reduced both neurogenic and SP-induced oedema (70% and 42% for neurogenic oedema, respectively; 49% and 46% for SP-induced oedema, respectively). 4 COX-2 mRNA was undetectable in saphenous nerves and paw skin biopsy samples, before and after saphenous nerve stimulation. 5 A mast cell stabilizer, cromolyn, and a H 1 receptor antagonist, mepyramine, signi®cantly inhibited neurogenic (51% and 43%, respectively) and SP-induced oedema (67% and 63%, respectively). 6 The co-injection of LOX inhibitors and compound 48/80 did not alter the eects of compound 48/80. Conversely, ethacrynic acid had a signi®cant potentiating eect. The pharmacological pro®le of the eect of COX inhibitors on compound 48/80-induced oedema was similar to that of neurogenic and SP-induced oedema. 7 The polysaccharide, fucoidan (an inhibitor of leukocyte rolling) did not aect neurogenic or SPinduced oedema. 8 Thus, (i) SP-induced leukotriene synthesis is involved in the development of neurogenic oedema in rat paw skin; (ii) this leukotriene-mediated plasma 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 signi®cant role in this process.

Mast cells: an expanding pathophysiological role from allergy to other disorders

“…Furthermore, neurogenically-generated mediators such as substance P and other inflammatory mediators may also degranulate the mast cells (Matsuda et al 1989), thus creating a bidirectional positive feedback-loop. The mast cell stabilizer, cromolyn, inhibits nociceptive behavior in the second phase of the formalin test (Parada et al 2001) and electrical stimulation of the saphenous nerve-induced neurogenic inflammation (Le Filliatre et al 2001). The degranulation of mast cells in close proximity to the nerves innervating the colonic mucosa is correlated with abdominal pain in IBS patients (Barbara et al 2004).…”

Contributions of Histamine, Prostanoids, and Neurokinins to Edema Elicited by Edema Toxin fromBacillus anthracis

“…via marginal ear vein to rabbits 60 min prior to i.d. toxin injections as described above (33,35). Celecoxib (75 mg/kg/day) was mixed with 2 ml of Nutri-Cal (Evsco Pharmaceuticals, Buena, NJ), a veterinary nutritional supplement containing 34.5% fat, to facilitate oral administration (64).…”

Histopathological and ultra-structural characterization of local neuromuscular damage induced by repeated phosphatidylcholine/deoxycholate injection

“…This involves the activation of endothelial cells increasing the gaps between them resulting in leakage of plasma and proteins causing edema. Increased substance P following nerve injury also leads to the activation of mast cells causing an increase in the release of histamine, leukotrines and prostagalandins (Le Filliatre et al, 2001). The association of mast cells and fibrosis has long been observed.…”

“…Studies had demonstrated the role of mast cell activation in the development of neurogenic edema and inflammation (Le Filliatre et al, 2001). Accumulating evidences showed that following nerve injury, the upregulation of substance P participate in the development of neuropathic pain and inflammation (Chen et al, 2015;Teodoro et al, 2013).…”