Pharmacological and molecular characterization of the mechanisms involved in prostaglandin E2-induced mouse paw edema

The present study evaluated some of the mechanisms underlying prostaglandin E-2 (PGE(2))-induced paw edema formation in mice. Intraplantar (i.pl.) injection of PGE(2) (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 PGE(2)-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 beta-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 PGE(2)-mediated paw edema. Conversely, the selective NK2, NK3, and calcitonin gene-related peptide (CGRP) CGRP(8-37) receptor antagonists all failed to interfere with PGE(2)-induced paw edema. The neonatal treatment of mice with capsaicin was also able to reduce PGE(2)-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 PGE(2)-mediated edema formation. The i.pl. injection of PGE(2) (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 PGE(2) 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 PGE(2)-mediated inflammatory responses in mice.