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

Abstract

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 ED 50 value of 0.42 nmol/paw. The coinjection of selec-L826266), but not EP 2 or EP 4 (all 10 nmol/paw), receptor antagonists significantly inhibited PGE 2 -induced paw edema. Like L826266, the PGE 2 -induced paw edema was markedly reduced by treatment with pertussis toxin and phospholipaseand the antagonist of vanilloid receptor (TRPV1) receptors 4Ј-chloro-3-methoxycinnamanilide (SB366791) (both 1 nmol/paw) also significantly inhibited PGE 2 -mediated paw edema. Conversely, the selective NK 2 , NK 3 , 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 NH 2 -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 EP 3 receptor antagonist L826266 (10 nmol/paw). Collectively, these findings indicate that edematogenic responses elicited by PGE 2 are mediated by EP 3 receptor activation, also involving the stimulation of PLC, PKC, and MAPKs pathways and the participation of TRPV1 and NK 1 receptors. These results make a considerable contribution to our comprehension of the mechanisms involved in PGE 2 -mediated inflammatory responses in mice.Inflammation is a complex physiological process that can be defined as a response to cellular and tissue injures caused by infections or physical and chemical stimuli. It is characterized by vasodilatation, increase of blood flow, and vascular permeability and cellular recruitment to the inflammatory site. These biochemical and cellular alterations are regulated This study was supported by grants

Antinociceptive activities of the methanol extract of the bulbs of Dioscorea bulbifera L. var sativa in mice is dependent of NO–cGMP–ATP-sensitive-K+ channel activation

“…The activation of EP 1 mediates, via Gq protein-protein kinase C (PKC), the increase of intracellular calcium which then triggers the release of sympathetic amines and the sympathetic pain (Loram et al, 2007). EP 2 and EP 4 are Gs coupled receptors that activate adenylyl cyclase which further increase cAMP activates protein kinase A (PKA) and the phosphorylation of numbers of ion channels (Claudino et al, 2006). The activation of EP 3 instead inhibits adenylyl cyclase as it is related to Gi protein (Loram et al, 2007) and may be antinociceptive.…”

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…In edema formation in rat and mouse skin, EP 3 receptor stimulation potently inhibited the response to zymosan-activated serum and plateletactivating factor (Ahluwalia and Perretti, 1994). PGE 2 -induced mouse paw edema was EP 3 receptor-mediated (Claudino et al, 2006). In the rat adjuvant arthritis model, synoviocytes expressed the EP 3 B isoform, which mediated FL-6 release (Kurihara et al, 2001).…”

Design, synthesis and structure–activity relationship studies of novel and diverse cyclooxygenase-2 inhibitors as anti-inflammatory drugs

“…As reported already 4,5,[122][123][124][125][126] , mechanisms of peripheralinflammatory oedema-formation by carrageenan comprise multiphasic processes in vivo that include the production of PGE 2 and PGI 2 (as inflammatory mediators) owing to COX-2 induction/ upregulation and COX-2 activity in the peripheral-inflammatory sites. Therefore, the mechanisms of actions of the oral antiinflammatory effects for the present series of novel {2-[(3-or 4-substituted)-benzoyl or cycloalkanecarbonyl]-(5-or 6-substituted)-1H-indol-3-yl}acetic acid analogues would be explicable by their inhibitory effects against PGE 2 and PGI 2 productions in the peripheral oedema-sites, directly depended on their intrinsic inhibitory potencies against COX-2, their physicochemical properties and their structural features, which is in accordance with the detailed mechanism-study for the previously reported analogues by Hayashi et al 25,104 .…”