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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA
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.)
Received for publication
February 10, 2006
Accepted
April 25, 2006.
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Abstract |
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-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) CGRP8-37 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.
). Prostanoids consisting of the prostaglandins and thromboxanes are rapidly synthesized via the cyclooxygenase pathway in a variety of cells in response to various stimuli such as inflammation (Funk, 2001; for review, see Bos et al., 2004; Hata and Breyer, 2004).
PGE2, a major cyclooxygenase product, exhibits a broad range of biological actions in diverse tissues through its binding to specific receptors on plasma membrane. These receptors belong to the family of G protein-coupled receptors, and they can be divided into four subtypes (EP1-4), each of which is encoded by distinct genes (Negishi et al., 1995). Whereas the EP1 receptor induces calcium mobilization by phospholipase C activation via Gq protein, EP2 and EP4 receptors are known to activate adenylyl cyclase via stimulatory G protein. On the other hand, the EP3 receptor reduces cAMP levels as it is coupled to inhibitory G proteins. In addition, the EP3 receptors are the only receptors to display multiple splice variants identified in several species (Namba et al., 1993; for review, see Kobayashi and Narumiya, 2002; Bos et al., 2004; Hata and Breyer, 2004).
PGE2 is generally considered as a key proinflammatory mediator, and its role has been extensively studied in several inflammatory events (Ikeda et al., 1975; Flower et al., 1976; Raud, 1990). Thus, high levels of PGE2 have been found in inflammatory exudates, and the injection of PGE2 directly into tissue has been shown to induce a number of classical sign of inflammation. However, despite the importance of PGE2 in this process being recognized, the receptor subtypes and the signaling pathways involved in the PGE2-mediated inflammatory actions remain to be further elucidated. In this regard, using pharmacological and molecular approaches, the present study aimed at investigating the receptor subtypes as well the possible signal transduction pathways involved in PGE2-induced paw edema formation in mice.
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Materials and Methods |
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Measurement of Mouse Paw Edema. Experiments were conducted according to the procedures described by Campos and Calixto (1995). In brief, the animals received a 20-µl intraplantar (i.pl.) injection, into the right hindpaw, of phosphate-buffered saline (PBS; composition 137 mM NaCl, 2.7 mM KCl, and 10 mM phosphate buffer) containing PGE2 (0.1-10 nmol/paw). The left paw received the same volume of PBS and was used as the control. The paw edema formation was measured by means of a plethysmometer (Ugo Basile, Comerio, Italy) at several time points (15, 30, 45, and 60 min) after the i.pl. injection of PGE2 and was expressed in microliters as the difference between the right and left paws.
Characterization of the Mechanisms Involved in PGE2-Induced Mouse Paw Edema. To evaluate the EP receptor subtypes involved in the edematogenic responses induced by PGE2, animals received an i.pl. injection of AH6809 (an EP2 receptor antagonist; 10 nmol/paw), L826266 (a selective EP3 receptor antagonist; 10 nmol/paw), or L161982 (an EP4 receptor antagonist; 10 nmol/paw) coinjected with PGE2 (3 nmol/paw). In a separate set of experiments, animals received L826266 (0.1-10 nmol/paw) 30 min before PGE2 (3 nmol/paw) injection.
In another experiment to assess the participation of pertussis toxin-sensitive G proteins in PGE2 paw edema formation, animals were pretreated with pertussis toxin (10 ng/paw) 20 min before PGE2 (3 nmol/paw) injection. The control group received the same volume (20 µl) of vehicle before PGE2 administration. In another experimental group, to test whether the phospholipase C (PLC) was involved in PGE2-induced paw edema, animals received an i.pl. injection of PGE2 (3 nmol/paw) in association with U-73122 (1 pmol/paw), a selective PLC antagonist.
In another experimental group, to evaluate the participation of sensorial neuropeptides and vanilloid receptors in PGE2-mediated mouse paw edema, animals received an i.pl. injection of the selective NK1 FK888 (1 nmol/paw), NK2 SR48968 (0.5 nmol/paw), NK3 SR142801 (1 nmol/paw), or calcitonin gene-related peptide (CGRP) CGRP8-37 (0.5 nmol/paw) receptor antagonists or the TRPV1 SB366791 (1 nmol/paw) receptor antagonist coinjected with PGE2 (3 nmol/paw).
To investigate to what extent some groups of kinases are involved in PGE2-induced edema formation in the mouse paw, we assessed the effects of coadministration of the following selective enzyme inhibitors with PGE2 (3 nmol/paw): H89 (PKA; 3 nmol/paw), GF109203X (PKC; 3 nmol/paw), SP600125 (JNK; 30 nmol/paw), PD98059 (mitogen-activated protein kinase kinase; 30 nmol/paw), and SB203580 (p38; 30 nmol/paw).
The doses of all inhibitors used in this study were chosen on the basis of literature data or preliminary experiments (Santos and Calixto, 1997; Beirith et al., 2003; Inoue et al., 2003; da Cunha et al., 2004; Ferreira et al., 2004, 2005).
Neonatal Capsaicin Treatment. To further explore the role of capsaicin-sensitive C fibers in PGE2-induced paw edema formation, mice were treated during the neonatal period (on the second day of life) with capsaicin (50 mg/kg, subcutaneously) or vehicle alone (10% ethanol, 10% Tween 80, and 80% PBS), as described previously (Gamse, 1982). Animals were used at 6 to 7 weeks after the neonatal administration of capsaicin or its vehicle (used as control). To discover whether the degeneration of capsaicin-sensitive primary afferent C fibers had occurred, we applied the wiping eye test described by Ikeda et al. (2001). In brief, 50 µl of 0.01% (w/v) capsaicin was instilled into one eye, and the number of wiping motions that occurred in the subsequent 1-min period was counted. The animals that wiped their eyes 5 times or less were used as the neonatal capsaicin-treated group. The edema was induced by i.pl. injection of PGE2 (3 nmol/paw) and measured as described above.
Preparation of Tissue for Western Blot Studies. The right paws of the mice were isolated at different times (5-60 min) after PGE2 treatment (3 nmol/paw). In another experimental group, 30 min before i.pl. injection of PGE2 (3 nmol/paw), the animals received an i.pl injection of L826266 (10 nmol/paw). Fifteen minutes after PGE2 treatment, the animals were killed, and the subcutaneous tissue of the paws was removed.
The subcutaneous tissue of the paws was rapidly removed and homogenized in an ice-cold buffer containing protease and phosphatase inhibitors (100 mM Tris-HCl, pH 7.4, 2 mM EDTA, 2 µg/ml aprotinin, 0.1 mM phenylmethanesulfonyl fluoride, 200 mM NaF, and 2 mM sodium orthovanadate). The homogenate was first centrifuged at 1000g for 10 min at 4°C. The pellet was discarded, and the supernatant was further centrifuged at 35,000g for 30 min at 4°C. The resulting supernatant was collected as a cytoplasm-rich fraction. Protein concentration was determined using a protein assay kit (Bio-Rad, Hercules, CA). The samples were aliquoted and stored at -80°C until Western blot analysis.
Western Blot Analysis. To assess the possible activation of MAPKs following PGE2 injection into the mouse paw, Western blot analysis was carried out as described previously (Ferreira et al., 2005) with minor modifications. Equivalent amounts of protein (40 µg for JNK and 70 µg for p38 of cytoplasm-rich fraction) were mixed with sample buffer (200 mM Tris, 10% glycerol, 2% SDS, 2.75 mM -mercaptoethanol, and 0.04% bromphenol blue) and boiled for 5 min. Proteins were separated in a 10% SDS-polyacrylamide gel by electrophoresis and transferred onto a polyvinylidene difluoride membrane, according to the manufacturer's instructions (Millipore Corporation, Billerica, MA). The membrane was blocked by incubation overnight with a 10% nonfat dry milk solution and then incubated with antiphosphorylated forms of JNK (phospho-JNK) or p38 (phospho-p38) antibodies. After washing, the membrane was incubated with adjusted peroxidase-coupled secondary antibodies. The immunocomplexes were visualized using the ECL chemiluminescence detection system (GE Healthcare, Little Chalfont, Buckinghamshire, UK). The membrane was then incubated for 10 min in a stripping buffer at room temperature and reincubated with an antibody against actin, which served as a loading control.
Drugs and Reagents. The following drugs and reagents were used: AH6809 (Cayman Chemical, Ann Arbor, MI); capsaicin, CGRP8-37 (CGRP fragment 8-37), H89, pertussis toxin, PGE2, and U-73122 (Sigma-Aldrich, St. Louis, MO); GF109203X, PD98059, SB203580, SB366791, and SP600125 (Tocris Cookson Inc., Ellisville, MO); and polyclonal antibodies antiactin and antiphosphorylated forms of JNK and p38 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA). FK888 was kindly provided by Fujisawa Pharmaceutical (Osaka, Japan). SR48968 and SR142801 were donated by Sanofi-Aventis (Bridgewater, NJ). L826266 and L161982 were kindly provided by Merck Frosst (Kirkland, QC, Canada).
Stock solutions for most drugs (0.1-1 M) were prepared in ethanol, except for AH6809 and CGRP8-37 that were made in a 1% NaHCO3 solution and distilled water, respectively. All drugs were stocked in siliconized plastic tubes and maintained at -18°C until use. Solutions of these drugs were prepared in PBS (137 mM NaCl, 2.7 mM KCl, and 10 mM phosphate buffer) to the desired concentration just before use. The final concentration of ethanol did not exceed 0.5%, which alone had no effect on PGE2-induced edema response. In addition, NaHCO3 alone also had no effect on PGE2-induced edema response.
Statistical Analysis. The results are presented as the mean ± S.E.M. of four to seven animals per group, except the mean ED50 or ID50 values (i.e., the dose of agonist necessary to produce 50% of the maximal edematogenic response or the dose of antagonists necessary to reduce the agonist response by 50% relative to the control value, respectively), which are reported as geometric means accompanied by their respective 95% confidence limits. The ED50 or ID50 values were calculated by use of the GraphPad Prism software (GraphPad Software Inc., San Diego, CA). The percentages of inhibition are reported as mean ± S.E.M. of inhibitions obtained for each individual experiment in relation to the control values. The ED50, ID50, and percentages of inhibition were calculated at the peak of PGE2-induced paw edema (30 min). Statistical comparison of the data were performed by analysis of variance (ANOVA) followed by Dunnett's or Student-Newman-Keuls tests or by Student's unpaired t test, as appropriate. P values less than 0.05 (P < 0.05) were considered significant.
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Results |
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Characterization of EP Receptor Subtypes in PGE2-Induced Mouse Paw Edema. PGE2-induced paw edema formation was significantly inhibited by coinjection of the selective EP3 receptor antagonist L826266 (10 nmol/paw), with a percentage of inhibition of 52.9 ± 8.3. On the other hand, the edematogenic response evoked by PGE2 was not significantly affected by the coadministration of either EP2 (AH6809; 10 nmol/paw) or EP4 (L161982; 10 nmol/paw) receptor antagonists (Fig. 2A). However, L826266 was not able to inhibit the edematogenic response induced by PGE2 at the 15-min time point. To elucidate whether the lack of inhibition was due to antagonist pharmacokinetics, we administered it locally 30 min before the edema induction. This pretreatment caused an accentuated inhibition (80.8 ± 5.5%) (Fig. 2A) of PGE2-mediated paw edema, an effect that was dependent on the used dose (0.1-10 nmol/paw) (Fig. 2B). The mean ID50 value calculated using the values obtained with the pretreatment was 0.36 (0.05-1.82) nmol/paw. Thus, these results indicate that edematogenic responses caused by PGE2 are probably mediated mainly through the activation of the EP3 receptor subtype.
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Involvement of PKC, PKA, and Mitogen-Activated Protein Kinases in PGE2-Induced Paw Edema Formation. Next, we investigated how the activation of some groups of kinases might be implicated in paw edema induced by PGE2 in mice. Figure 5, A and B, demonstrates that the i.pl. coinjection of the selective inhibitors of p38 (SB203580; 30 nmol/paw), JNK (SP600125; 30 nmol/paw), ERK (PD98059; 30 nmol/paw), and PKC (GF109203X; 3 nmol/paw), all significantly reduced PGE2-induced paw edema formation. The percentages of inhibition observed for these drugs were 48.6 ± 2.2, 51.5 ± 4.9, 64.0 ± 3.6, and 54.5 ± 5.8, respectively. In contrast, the coinjection of the selective inhibitor of PKA (H89; 3 nmol/paw) had no significant effect on PGE2 response.
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The i.pl. injection of PGE2 (3 nmol/paw) resulted in a marked and time-dependent activation of MAPKs. A statistically significant increase in phosphorylation levels of JNK was observed from 5 to 30 min following PGE2 administration (Fig. 6A). Moreover, p38 MAPK phosphorylation was significant from 15 to 60 min after PGE2 injection (Fig. 6B). We did not detect any alteration in actin expression after PGE2 injection.
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Discussion |
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; Ikeda et al., 1975; Flower et al., 1976; Raud, 1990). Interestingly, the present data allow us to suggest that PGE2-elicited paw edema in mice is mainly, if not solely, mediated by the activation of EP3 receptors. This conclusion derives from the results indicating that edema formation induced by PGE2 injection is markedly prevented by the selective EP3 L826266, but not the EP2 AH6809 or EP4 L161982 receptor antagonists. In fact, it has been recently demonstrated that edema formation and plasmatic extravasation induced by the topical application of arachidonic acid is found significantly decreased in mice with genic deletion of EP3 receptors, whereas these responses remain unaffected in knockout mice for EP1, EP2, or EP4 receptors (Goulet et al., 2004) In addition, Yuhki et al. (2004) showed that IP, EP2, and EP3, but not EP1 or EP4, receptor subtypes are largely implicated in exudate formation in the model of pleurisy induced by carrageenan in the mouse. Notably, we have also observed that the EP3 receptor antagonist L826266 consistently inhibits carrageenan-induced edema in mice, to the same extent that it is able to reduce PGE2-mediated edema formation (data not shown). Although our data visibly point to the EP3 receptor as being mainly responsible for the edematogenic effect of PGE2 in the mouse paw, we cannot completely discard the participation of the EP1 receptor in this response, because no selective EP1 receptor antagonist is currently available for mice. This possibility remains to be further evaluated in future studies.
The EP3 receptor is distributed throughout most mouse tissues (Narumiya et al., 1999). Its alternative splicing forms are capable of inducing a broad range of effects (Bos et al., 2004). Murine EP3
, EP3, and EP3
receptors usually activate inhibitory G proteins, but they may also interact with Gs and G13 proteins (for reviews, see Hatae et al., 2002; Hata and Breyer, 2004). It was first affirmed that EP3 receptor would be able to decrease the adenylyl cyclase activity (reducing the cAMP production) through an interaction with the Gi subunit. Furthermore, the stimulation of PLC by EP3 receptor was reported to induce the accumulation of inositol triphosphate and diacylglycerol that, in turn, promoted intracellular Ca2+ mobilization and PKC activation (Irie et al., 1994). Moreover, it has been hypothesized that subunits of Gi might stimulate PLC and activate p21ras (Irie et al., 1994; Burkey and Regan, 1995). The results of the present study confirm and also extend these previous findings by demonstrating that the pretreatment with pertussis toxin significantly inhibited PGE2-induced paw edema. Furthermore, PGE2-induced paw edema formation was significantly inhibited by coinjection of the selective PLC inhibitor U-73122. We might assume that one or more of the above-mentioned signaling pathways are involved in EP3 receptor-mediated PGE2-induced responses in the mouse paw.
Another interesting aspect investigated in the present study was the possible participation of certain groups of kinases in the mouse paw edema induced by PGE2. Our results demonstrate that the selective PKC blocker GF109203X, but not the PKA inhibitor H89, was able to consistently reduce PGE2-induced mouse paw edema. Additional sets of experiments also indicated the relevance of MAPKs in our model, because the selective JNK SP600125, ERK PD98059, or p38 SB203580 inhibitors were all markedly effective in reducing PGE2-induced edema formation. The functional results were confirmed by Western blot analysis, which indicated that i.pl. injection of PGE2 resulted in a marked activation of PKC (our unpublished data), JNK and p38 MAPKs in the mouse paw. Of interest, the increased expression of MAPKs, but not PKC, induced by PGE2, seems to be driven by the activation of EP3 receptor subtype, because this response was almost completely prevented by the selective EP3 receptor antagonist. However, we cannot discard the hypothesis that EP3 receptor may activate other forms of PKC. Therefore, we might suggest that EP3-mediated PGE2 edematogenic responses in the mouse paw involve the coordinated activation of PKC, but not PKC isoform, and MAPKs. In this regard, there are reports in the literature demonstrating that stimulation of PKC is able to activate the ERK signaling pathway (Qiu and Leslie, 1994; Vlahos et al., 2003).
The activation of peripheral terminals of sensory fibers, especially C fibers, causes the release of neuropeptides (such as tachykinins) both peripherally and in the dorsal spinal cord (Holzer, 1998). These inflammatory mediators, particularly substance P, act on target cells in the periphery, producing the classic signals of inflammation in a phenomenon known as "neurogenic inflammation" (Holzer, 1998; Richardson and Vasko, 2002). The present study also analyzed the possible role played by sensory fibers in PGE2-induced paw edema. Capsaicin is a pharmacological tool that produces the selective degeneration of C and some A
fibers, associated with the irreversible loss of more than 80% of small-diameter sensory neuron cell bodies (for review, see Holzer, 1991). Our results demonstrated that neonatal treatment with capsaicin was able to inhibit PGE2-induced mouse paw edema, suggesting that stimulation of primary sensory fibers is an important event for PGE2 inflammatory responses. In addition, we showed that coinjection of the selective NK1 FK888, but not NK2 SR48969, NK3 SR142801, or CGRP CGRP8-37 receptor antagonists, significantly reduced PGE2-evoked edema formation. Consequently, it is possible to conclude that proedematogenic effects of PGE2 in the mouse paw are mediated, at least partially, by the release of tachykinins, probably substance P, acting on NK1 receptors. In fact, White (1996) has shown that PGE2 is capable of releasing substance P from cultured rat sensory neurons. The colocalization of tachykinin and TRPV1 receptors (nonselective cation channels expressed predominantly in small-diameter sensory fibers) strongly suggests the involvement of the latter in the PGE2-induced edematogenic response. The TRPV1 receptor is exogenously activated by the pungent plant-derived compound capsaicin, but it is also endogenously stimulated by protons, heat, and some lipid-derived mediators (for review, see Calixto et al., 2005). It is now well known that TRPV1 activation augments the release of neuropeptides in a calcium-dependent manner (Bevan and Geppetti, 1994; Kessler et al., 1999). We found that, at least in part, PGE2-induced edematogenic response in the mouse paw is associated with the activation of TRPV1. This conclusion derives from the results indicating that the coinjection of the selective TRPV1 receptor antagonist SB366791 significantly inhibited the PGE2-induced paw edema. Recent evidence has suggested that regulation and activation of TRPV1 are defined by complex mechanisms such as phospholipid-mediated inhibition and phosphorylation (Premkumar and Ahern, 2000; Chuang et al., 2001). It is noteworthy that TRPV1 can be modulated by the PKA and PKC phosphorylation (Lopshire and Nicol 1998; Cesare et al., 1999). Interestingly, it has recently been shown that functional interaction of TRPV1 with PGE2 occurs through a PKC-dependent mechanism by coupling of EP1 receptor (Moriyama et al., 2005). Thus, our results allow us to suggest that PGE2 might modulate TRPV1 through the PKC-dependent mechanisms. Whether MAPKs are associated with the activation of sensory fibers following EP3 receptor activation by PGE2 remains to be further assessed.
Together, the present results provide convincing experimental evidence indicating that PGE2 induces paw edema in mice via the stimulation of EP3 receptors, in a process dependent on the activation of TRPV1 and NK1 receptors as well as PKC and MAPKs. These findings help to elucidate the possible mechanisms underlying PGE2-elicited inflammatory responses in mice and point to EP3 receptor antagonists as possible therapeutic options for treating inflammatory disorders.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: PGE2, prostaglandin E2; EP, E-prostanoid; i.pl., intraplantar; PBS, phosphate-buffered saline; AH6809, 6-isopropoxy-9-oxoxanthene-2-carboxylic acid; L826266, (2E)-N-[(5-bromo-2-methoxyphenyl)sulfonyl]-3-[5-chloro-2-(2-naphthylmethyl)phenyl]acrylamide; L161982, N-{[4'-({3-butyl-5-oxo-1-[2-(trifluoromethyl) phenyl]-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl) biphenyl-2-yl]sulfonyl}-3-methylthiophene-2-carboxamide; PLC, phospholipase C; U-73122, 1-[6-[[17-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione; NK, neurokinin; CGRP, calcitonin gene-related peptide; PD98059, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; SB203580, 4-[5-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]pyridine); SB366791, 4'-chloro-3-methoxycinnamanilide; SP600125, anthra[1,9-cd]pyrazol-6-(2H)-one; FK888, N-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methyl-N-phenyl-methyl-3-(2-aphthyl)-L-alaninamide; SR48968, (S)-N-methyl-(N[4-acetylamino-4-phenylpiperidine)-2-(3,4-dichlorophenyl)butyl]benzamide; SR142801, (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)-piperiden-3-yl)propyl)-4-phenilpipedidin-4-yl)-N-methyl-acetamide; TRPV1, vanilloid receptor; H89, N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline; PKA, protein kinase A; GF109203X, 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride; PKC, protein kinase C; JNK, c-Jun NH2-terminal kinase; ANOVA, analysis of variance; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase.
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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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Beirith A, Santos AR, and Calixto JB (2003) The role of neuropeptides and capsaicin-sensitive fibres in glutamate-induced nociception and paw oedema in mice. Brain Res 969: 110-116.[CrossRef][Medline]
Bevan S and Geppetti P (1994) Protons: small stimulants of capsaicin-sensitive sensory nerves. Trends Neurosci 17: 509-512.[CrossRef][Medline]
Bos CL, Richel DJ, Ritsema T, Peppelenbosch MP, and Versteeg HH (2004) Prostanoids and prostanoid receptors in signal transduction. Int J Biochem Cell Biol 36: 1187-1205.[CrossRef][Medline]
Burkey TH and Regan JW (1995) Activation of mitogen-activated protein kinase by the human prostaglandin EP3A receptor. Biochem Biophys Res Commun 211: 152-158.[CrossRef][Medline]
Campos MM and Calixto JB (1995) Involvement of B1 and B2 receptors in bradykinin-induced rat paw oedema. Br J Pharmacol 114: 1005-1013.[Medline]
Calixto JB, Kassuya CA, Andre E, and Ferreira J (2005) Contribution of natural products to the discovery of the transient receptor potential (TRP) channels family and their functions. Pharmacol Ther 106: 179-208.[CrossRef][Medline]
Cesare P, Dekker LV, Sardini A, Parker PJ, and McNaughton PA (1999) Specific involvement of PKC-epsilon in sensitization of the neuronal response to painful heat. Neuron 23: 617-624.[CrossRef][Medline]
Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, and Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature (Lond) 411: 957-962.[CrossRef][Medline]
da Cunha JM, Rae GA, Ferreira SH, and Cunha F de Q (2004) Endothelins induce ETB receptor-mediated mechanical hypernociception in rat hindpaw: roles of cAMP and protein kinase C. Eur J Pharmacol 501: 87-94.[CrossRef][Medline]
Ferreira J, da Silva GL, and Calixto JB (2004) Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice. Br J Pharmacol 141: 787-794.[CrossRef][Medline]
Ferreira J, Triches KM, Medeiros R, and Calixto JB (2005) Mechanisms involved in the nociception produced by peripheral protein kinase C activation in mice. Pain 117: 171-181.[CrossRef][Medline]
Flower RJ, Harvey EA, and Kingston WP (1976) Inflammatory effects of prostaglandin D2 in rat and human skin. Br J Pharmacol 56: 229-233.[Medline]
Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science (Wash DC) 294: 1871-1875.
Gamse R (1982) Capsaicin and nociception in the rat and mouse. Possible role of substance P. Naunyn-Schmiedeberg's Arch Pharmacol 320: 205-216.[CrossRef][Medline]
Goulet JL, Pace AJ, Key ML, Byrum RS, Nguyen M, Tilley SL, Morham SG, Langenbach R, Stock JL, McNeish JD, et al. (2004) E-prostanoid-3 receptors mediate the proinflammatory actions of prostaglandin E2 in acute cutaneous inflammation. J Immunol 173: 1321-1326.
Hata AN and Breyer RM (2004) Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther 103: 147-166.[CrossRef][Medline]
Hatae N, Sugimoto Y, and Ichikawa A (2002) Prostaglandin receptors: advances in the study of EP3 receptor signaling. J Biochem (Tokyo) 131: 781-784.
Holzer P (1991) Capsaicin: cellular targets, mechanisms of action and selectivity for thin sensory neurons. Pharmacol Rev 43: 143-201.[Medline]
Holzer P (1998) Neurogenic vasodilatation and plasma leakage in the skin. Gen Pharmacol 30: 5-11.[Medline]
Ikeda K, Tanaka K, and Katori M (1975) Potentiation of bradykinin-induced vascular permeability increase by prostaglandin E2 and arachidonic acid in rabbit skin. Prostaglandins 10: 747-758.[CrossRef][Medline]
Ikeda Y, Ueno A, Naraba H, and Oh-ishi S (2001) Involvement of vanilloid receptor VR1 and prostanoids in the acid-induced writhing responses of mice. Life Sci 69: 2911-2919.[CrossRef][Medline]
Inoue M, Kawashima T, Allen RG, and Ueda H (2003) Nocistatin and prepronociceptin/orphanin FQ 160-187 cause nociception through activation of Gi/o in capsaicin-sensitive and of Gs in capsaicin-insensitive nociceptors, respectively. J Pharmacol Exp Ther 306: 141-146.
Irie A, Segi E, Sugimoto Y, Ichikawa A, and Negishi M (1994) Mouse prostaglandin E receptor EP3 subtype mediates calcium signals via Gi in cDNA-transfected Chinese hamster ovary cells. Biochem Biophys Res Commun 204: 303-309.[CrossRef][Medline]
Kessler F, Habelt C, Averbeck B, Reeh PW, and Kress M (1999) Heat-induced release of CGRP from isolated rat skin and effects of bradykinin and the protein kinase C activator PMA. Pain 83: 289-295.[CrossRef][Medline]
Kobayashi T and Narumiya S (2002) Function of prostanoid receptors: studies on knockout mice. Prostaglandins Other Lipid Mediat 68-69: 557-573.[Medline]
Lopshire JC and Nicol GD (1998) The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell and single-channel studies. J Neurosci 18: 6081-6092.
Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, and Tominaga M (2005) Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain 1: 1-13.[CrossRef][Medline]
Namba T, Sugimoto Y, Negishi M, Irie A, Ushikubi F, Kakizuka A, Ito S, Ichikawa A, and Narumiya S (1993) Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP3 determines G-protein specificity. Nature (Lond) 365: 166-170.[CrossRef][Medline]
Narumiya S, Sugimoto Y, and Ushikubi F (1999) Prostanoid receptors: structures, properties and functions. Physiol Rev 79: 1193-1226.
Negishi M, Sugimoto Y, and Ichikawa (1995) Prostaglandin E receptors. J Lipid Mediat Cell Signal 12: 379-391.[CrossRef][Medline]
Premkumar LS and Ahern GP (2000) Induction of vanilloid receptor channel activity by protein kinase C. Nature (Lond) 408: 985-990.[CrossRef][Medline]
Qiu ZH and Leslie CC (1994) Protein kinase C-dependent and -independent pathways of mitogen-activated protein kinase activation in macrophages by stimuli that activate phospholipase A2. J Biol Chem 269: 19480-19487.
Raud J (1990) Vasodilatation and inhibition of mediator release represent two distinct mechanisms for prostaglandin modulation of acute mast cell-dependent inflammation. Br J Pharmacol 99: 449-454.[Medline]
Richardson JD and Vasko MR (2002) Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther 302: 839-845.
Santos AR and Calixto JB (1997) Further evidence for the involvement of tachykinin receptor subtypes in formalin and capsaicin models of pain in mice. Neuropeptides 31: 381-389.[CrossRef][Medline]
Vlahos CJ, McDowell SA, and Clerk A (2003) Kinases as therapeutic targets for heart failure. Nat Rev Drug Discov 2: 99-113.[CrossRef][Medline]
White DM (1996) Mechanism of prostaglandin E2-induced substance P release from cultured sensory neurons. Neuroscience 70: 561-565.[CrossRef][Medline]
Williams TJ and Morley J (1973) Prostaglandins as potentiators of increased vascular permeability in inflammation. Nature (Lond) 246: 215-217.[CrossRef][Medline]
Yuhki K, Ueno A, Naraba H, Kojima F, Ushikubi F, Narumiya S, and Oh-ishi S (2004) Prostaglandin receptors EP2, EP3 and IP mediate exudate formation in carrageenin-induced mouse pleurisy. J Pharmacol Exp Ther 311: 1218-1224.
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