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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Pharmacological and Molecular Characterization of the Mechanisms Involved in Prostaglandin E₂-Induced Mouse Paw Edema

Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil (R.F.C., C.A.L.K., J.B.C.); and Department of Chemistry, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil (J.F.)

The present study evaluated some of the mechanisms underlying prostaglandin E₂ (PGE₂)-induced paw edema formation in mice. Intraplantar (i.pl.) injection of PGE₂ (0.10-10.0 nmol/paw) into the hindpaw elicited a dose-related edema formation, with a mean ED₅₀ value of 0.42 nmol/paw. The coinjection of selective E-prostanoid (EP)₃ [(2E)-N-[(5-bromo-2-methoxyphenyl)-sulfonyl]-3-[5-chloro-2-(2-naphthylmethyl)phenyl]acrylamide; L826266), but not EP₂ or EP₄ (all 10 nmol/paw), receptor antagonists significantly inhibited PGE₂-induced paw edema. Like L826266, the PGE₂-induced paw edema was markedly reduced by treatment with pertussis toxin and phospholipase C (PLC) inhibitor 1-[6-[[17-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122). Likewise, the selective neurokinin (NK)₁ receptor antagonist N-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methyl-N-phenyl-methyl-3-(2-aphthyl)-L-alaninamide (FK888) and the antagonist of vanilloid receptor (TRPV1) receptors 4'-chloro-3-methoxycinnamanilide (SB366791) (both 1 nmol/paw) also significantly inhibited PGE₂-mediated paw edema. Conversely, the selective NK₂, NK₃, and calcitonin gene-related peptide (CGRP) CGRP_8-37 receptor antagonists all failed to interfere with PGE₂-induced paw edema. The neonatal treatment of mice with capsaicin was also able to reduce PGE₂-induced paw edema. The inhibitors of protein kinase C (PKC) 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X) and mitogen protein-activated kinases (MAPKs; 30 nmol/paw) c-Jun NH₂-terminal kinase (JNK) (anthra[1,9-cd]pyrazol-6(2H)-one; SP600125), extracellular signal-regulated kinase (PD98059), and p38 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SB203580], but not protein kinase A, markedly decreased the PGE₂-mediated edema formation. The i.pl. injection of PGE₂ (3 nmol/paw) induced a significant activation of MAPKs, namely, JNK and p38, an effect that was largely prevented by the selective EP₃ receptor antagonist L826266 (10 nmol/paw). Collectively, these findings indicate that edematogenic responses elicited by PGE₂ are mediated by EP₃ receptor activation, also involving the stimulation of PLC, PKC, and MAPKs pathways and the participation of TRPV1 and NK₁ receptors. These results make a considerable contribution to our comprehension of the mechanisms involved in PGE₂-mediated inflammatory responses in mice.

Address correspondence to: Dr. João Batista Calixto, Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Universitário-Trindade, Bloco D-CCB-Cx, Postal 476-CEP, 88049-900-Florianópolis, Santa Catarina, Brazil. E-mail: calixto{at}farmaco.ufsc.br or calixto3{at}terra.com.br

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