RESUMO
BACKGROUND: Kinins, with bradykinin and des-Arg(9)-bradykinin being the most important ones, are pro-inflammatory peptides released after tissue injury including stroke. Although the actions of bradykinin are in general well characterized; it remains controversial whether the effects of bradykinin are beneficial or not. Kinin-B2 receptor activation participates in various physiological processes including hypotension, neurotransmission and neuronal differentiation. The bradykinin metabolite des-Arg(9)-bradykinin as well as Lys-des-Arg(9)-bradykinin activates the kinin-B1 receptor known to be expressed under inflammatory conditions. We have investigated the effects of kinin-B1 and B2 receptor activation on N-methyl-D-aspartate (NMDA)-induced excitotoxicity measured as decreased capacity to produce synaptically evoked population spikes in the CA1 area of rat hippocampal slices. PRINCIPAL FINDINGS: Bradykinin at 10 nM and 1 µM concentrations triggered a neuroprotective cascade via kinin-B2 receptor activation which conferred protection against NMDA-induced excitotoxicity. Recovery of population spikes induced by 10 nM bradykinin was completely abolished when the peptide was co-applied with the selective kinin-B2 receptor antagonist HOE-140. Kinin-B2 receptor activation promoted survival of hippocampal neurons via phosphatidylinositol 3-kinase, while MEK/MAPK signaling was not involved in protection against NMDA-evoked excitotoxic effects. However, 100 nM Lys-des-Arg(9)-bradykinin, a potent kinin-B1 receptor agonist, reversed bradykinin-induced population spike recovery. The inhibition of population spikes recovery was reversed by PD98059, showing that MEK/MAPK was involved in the induction of apoptosis mediated by the B1 receptor. CONCLUSIONS: Bradykinin exerted protection against NMDA-induced excitotoxicity which is reversed in the presence of a kinin-B1 receptor agonist. As bradykinin is converted to the kinin-B1 receptor metabolite des-Arg(9)-bradykinin by carboxypeptidases, present in different areas including in brain, our results provide a mechanism for the neuroprotective effect in vitro despite of the deleterious effect observed in vivo.
Assuntos
Bradicinina/toxicidade , N-Metilaspartato , Receptor B1 da Bradicinina/agonistas , Receptor B2 da Bradicinina/fisiologia , Animais , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Química Encefálica , Região CA1 Hipocampal , Carboxipeptidases/metabolismo , Fármacos Neuroprotetores , Ratos , Receptor B1 da Bradicinina/fisiologiaRESUMO
Focal and segmental glomerulosclerosis (FSGS) is one of the most important causes of end-stage renal failure. The bradykinin B1 receptor has been associated with tissue inflammation and renal fibrosis. To test for a role of the bradykinin B1 receptor in podocyte injury, we pharmacologically modulated its activity at different time points in an adriamycin-induced mouse model of FSGS. Estimated albuminuria and urinary protein to creatinine ratios correlated with podocytopathy. Adriamycin injection led to loss of body weight, proteinuria, and upregulation of B1 receptor mRNA. Early treatment with a B1 antagonist reduced albuminuria and glomerulosclerosis, and inhibited the adriamycin-induced downregulation of podocin, nephrin, and α-actinin-4 expression. Moreover, delayed treatment with antagonist also induced podocyte protection. Conversely, a B1 agonist aggravated renal dysfunction and even further suppressed the levels of podocyte-related molecules. Thus, we propose that kinin has a crucial role in the pathogenesis of FSGS operating through bradykinin B1 receptor signaling.
Assuntos
Bradicinina/análogos & derivados , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Podócitos/efeitos dos fármacos , Receptor B1 da Bradicinina/agonistas , Transdução de Sinais/efeitos dos fármacos , Actinina/metabolismo , Albuminúria/induzido quimicamente , Albuminúria/metabolismo , Albuminúria/prevenção & controle , Animais , Bradicinina/farmacologia , Bradicinina/toxicidade , Antagonistas de Receptor B1 da Bradicinina , Modelos Animais de Doenças , Doxorrubicina , Regulação da Expressão Gênica/efeitos dos fármacos , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Glomerulosclerose Segmentar e Focal/prevenção & controle , Heme Oxigenase-1/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Podócitos/metabolismo , Podócitos/patologia , RNA Mensageiro/metabolismo , Receptor B1 da Bradicinina/genética , Receptor B1 da Bradicinina/metabolismo , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
The present work explored the antinociceptive effects of the flavonoid myricitrin in models of overt nociception triggered by intraplantar injection of chemical algogens into the hind paw of mice. The nociception induced by bradykinin (3 nmol/paw i.pl.) was abolished by prior treatment with myricitrin (10-100mg/kg, i.p.) with ID(50) of 12.4 (8.5-18.1)mg/kg. In sharp contrast, myricitrin failed to affect the nociception elicited by prostaglandin E(2) (3 nmol/paw i.pl.). Cinnamaldehyde (10 nmol/paw i.pl.)-induced nociception was reduced by myricitrin (100mg/kg, i.p.) and camphor (7.6 mg/kg,s.c.) in 43±10% and 57±8%, respectively. Myricitrin (30-100mg/kg, i.p.) and amiloride (100mg/kg, i.p.) inhibited nociceptive responses induced by acidified saline (pH 5/paw i.pl.), with ID(50) of 22.0 (16.1-30.0)mg/kg and inhibition of 71±6% and 64±5%, respectively. Moreover, myricitrin (10-30 mg/kg, i.p.) and ruthenium red (3mg/kg, i.p.) significantly reduced the nociception induced by menthol (1.2 µmol/paw i.pl.) with the mean ID(50) of 2.4 (1.5-3.7)mg/kg and inhibition of 95±3% and 51±7%, respectively. In addition, myricitrin administration (30 and 100mg/kg, i.p.) markedly reduced menthol-induced mechanical allodynia. However, myricitrin (100mg/kg, i.p.) prevented (only in time of 60 min) cold allodynia induced by menthol. Collectively, the present results extend prior data and show that myricitrin promotes potent antinociception, an action that is likely mediated by an inhibition of the activation of nociceptors by bradykinin and TRPs agonist (i.e. cinnamaldehyde, acidified saline and menthol), probably via inhibition of PKC pathways. Thus, myricitrin could constitute an attractive molecule of interest for the development of new analgesic drugs.
Assuntos
Analgésicos não Narcóticos/uso terapêutico , Flavonoides/uso terapêutico , Modelos Químicos , Dor/tratamento farmacológico , Acroleína/análogos & derivados , Acroleína/toxicidade , Amilorida/uso terapêutico , Animais , Bradicinina/toxicidade , Cânfora/uso terapêutico , Dinoprostona/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Lateralidade Funcional/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Dor/induzido quimicamente , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Rutênio Vermelho/uso terapêuticoRESUMO
UNLABELLED: The aim of this study was to investigate the anti-inflammatory effects and the mechanism of action of the aqueous extracts obtained from rhizomes, leaves and inflorescences of Solidago chilensis in the mouse model of pleurisy. The extracts were prepared by infusion and were lyophilized. RESULTS: The aqueous extracts of rhizomes, leaves or inflorescences inhibited leukocytes, neutrophils and exudation (P<0.05) in the inflammation induced by carrageenan. The rhizomes aqueous extract, butanolic and aqueous residual fractions inhibited leukocytes, neutrophils, myeloperoxidase, adenosine-deaminase, and tumor necrosis factor alpha levels in the inflammation induced by carrageenan (P<0.05). The rhizome aqueous extract and butanolic fraction also inhibited exudation, nitric oxide, and interleukin-1 beta levels (P<0.05). The rhizomes aqueous extract and its two derived fractions reduced leukocytes and mononuclears in the pleurisy induced by bradykinin, histamine, or substance P (P<0.05) and neutrophils in the pleurisy induced by histamine or substance P (P<0.05). Only aqueous residual fraction inhibited neutrophils induced by bradykinin (P<0.05). CONCLUSION: Solidago chilensis aqueous extracts from leaves, inflorescences and rhizomes demonstrated an important anti-inflammatory effect, inhibiting cells in the inflammation caused by carrageenan. In addition, the rhizomes aqueous extract and its derived fractions also decreased pro-inflammatory mediators release into the site of the inflammatory process. The rhizomes aqueous extract and the butanolic fraction showed more evident anti-inflammatory actions.
Assuntos
Anti-Inflamatórios/farmacologia , Extratos Vegetais/farmacologia , Pleurisia/prevenção & controle , Solidago/química , Adenosina Desaminase/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Bradicinina/administração & dosagem , Bradicinina/toxicidade , Butanóis/química , Carragenina/administração & dosagem , Carragenina/toxicidade , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Flores/química , Histamina/administração & dosagem , Histamina/toxicidade , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/prevenção & controle , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Camundongos , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Peroxidase/metabolismo , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Pleurisia/induzido quimicamente , Pleurisia/metabolismo , Rizoma/química , Substância P/administração & dosagem , Substância P/toxicidade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
INTRODUCTION: Tacrolimus is an antibiotic macrolide with immunosuppressant properties isolated from Streptomyces tsukubaensis. OBJECTIVES: This study evaluated whether the acute and systemic administration of Tacrolimus significantly interfered in leukocyte migration, exudation, myeloperoxidase and adenosine-deaminase and nitric oxide levels, as well as Interleukin-1 (IL-1beta) and tumor necrosis factor alpha (TNFalpha) levels in a mouse model of pleurisy in comparison to those obtained with dexamethasone. MATERIALS AND METHODS: Pleurisy was induced by carrageenan (Cg, 1%), bradykinin (BK, 10 nmol), histamine (HIS, 1 micromol) or substance P (PS, 20 nmol) administered by intrapleural route (ipl.) and the inflammatory parameters (cell migration and exudation) were analyzed 4 h after. In the model of pleurisy induced by carrageenan, other markers in the pleural fluid, such as cytokines (TNFalpha and Il-1beta), nitrite/nitrate (NOx), myeloperoxidase (MPO) and adenosine-deaminase (ADA) levels, were also studied. Dexamethaseone (0.5 mg/kg, i.p., 0.5 h before) was also analyzed in all protocols. RESULTS: In the pleurisy induced by carrageenan, Tacrolimus (1 mg/kg, i.p.) and dexamethasone (0.5 mg/kg, i.p.) administered 0.5 h before caused a significant decrease in leukocytes, neutrophils and exudation (P < 0.01). Under the same conditions, Tacrolimus and dexamethasone did not modify the blood's white or red cells (P > 0.05). Tacrolimus showed a long lasting antiinflammatory effect, inhibiting leukocytes and neutrophils for up to 24 h (P < 0.01), whereas the inhibition of exudation was less marked (up to 2 h) (P < 0.01). These drugs caused a marked reduction in MPO activity, as well as IL-1beta and TNFalpha levels (P < 0.01), but only Tacrolimus inhibited ADA activity (P < 0.01). On the other hand, dexamethasone, but not Tacrolimus, inhibited NOx levels (P < 0.01). In the same conditions, Tacrolimus significantly inhibited cell migration induced by either bradykinin, histamine or substance P (P < 0.05). In a similar manner, dexamethasone inhibited leukocyte influx induced by bradykinin and histamine (P < 0.05). Regarding exudation effects, dexamethasone markedly inhibited this parameter induced by BK, HIS or SP, whereas Tacrolimus only inhibited exudation caused by HIS (P < 0.05). CONCLUSIONS: The results of the present work indicate that Tacrolimus showed important antiinflammatory properties against pleurisy in mice that are different from those caused by dexamethasone. The inhibition of proinflammatory cytokine (TNFalpha, IL-1beta), enzyme (myeloperoxidase, adenosine-deaminase) and mediator (bradykinin, histamine, substance P) release and/or action appears to account for Tacrolimus's actions.
Assuntos
Imunossupressores/administração & dosagem , Pleurisia/prevenção & controle , Tacrolimo/administração & dosagem , Adenosina Desaminase/sangue , Adenosina Desaminase/imunologia , Animais , Antibacterianos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Bradicinina/farmacologia , Bradicinina/toxicidade , Carragenina/farmacologia , Carragenina/toxicidade , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Dexametasona/administração & dosagem , Modelos Animais de Doenças , Histamina/farmacologia , Histamina/toxicidade , Histamínicos/farmacologia , Histamínicos/toxicidade , Humanos , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/prevenção & controle , Interleucina-1/sangue , Interleucina-1/imunologia , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/imunologia , Óxido Nítrico/sangue , Óxido Nítrico/imunologia , Peroxidase/sangue , Peroxidase/imunologia , Pleurisia/sangue , Pleurisia/induzido quimicamente , Pleurisia/imunologia , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/imunologia , Vasodilatadores/farmacologia , Vasodilatadores/toxicidadeRESUMO
The anti-hyperalgesic action, antinociception, and also the possible mechanisms involved in the action of gallic acid ethyl ester (GAEE) isolated from the aerial part of Phyllanthus urinaria, have been investigated in different models of chemical, mechanical and thermal nociception in mice and rats. GAEE given by intraperitoneal (i.p.), oral (p.o.), intrathecal (i.t.) or by intracerebroventricular (i.c.v.) routes produced dose-related antinociception when assessed against chemical nociception in mice. GAEE significantly inhibited the hyperalgesia induced by bradykinin or substance P in rat paw, but did not affect the hyperalgesia caused by carrageenan or prostaglandin E2. Furthermore, GAEE, in contrast to morphine, was completely ineffective in the hot-plate test in mice. The antinociception produced by GAEE (i.p.) in the formalin test was significantly reversed by i.c.v. treatment of animals with pertussis toxin and by i.t. administration of K+ channel blockers such as apamin, charybdotoxin or glibenclamide, but not by tetraethylammonium. In contrast, GAEE (i.p.) antinociception was unaffected by i.p. treatment of animals with naloxone or by nitric oxide precursor, L-arginine, and this action was not secondary to its anti-inflammatory effect, nor was it associated with non-specific effects such as muscle relaxation or sedation. Thus, GAEE produces dose-dependent and pronounced systemic, spinal and supraspinal antinociception in mice, probably via activation of K + channels and by a Gi/o pertussis toxin-sensitive mechanism.
Assuntos
Analgésicos/farmacologia , Proteínas de Ligação ao GTP/fisiologia , Ácido Gálico/farmacologia , Canais de Potássio/fisiologia , Animais , Bradicinina/toxicidade , Relação Dose-Resposta a Droga , Interações Medicamentosas , Pé/fisiologia , Ácido Gálico/análogos & derivados , Ácido Gálico/isolamento & purificação , Masculino , Camundongos , Relaxamento Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Medição da Dor/métodos , Toxina Pertussis , Ratos , Ratos Wistar , Substância P/toxicidade , Fatores de Tempo , Fatores de Virulência de Bordetella/toxicidadeRESUMO
This study analyses the anti-hyperalgesic properties of the hydroalcoholic extract (HE) and the sesquiterpene polygodial isolated from the barks of Drymis winteri (Winteraceae). The HE (10 to 60 mg kg(-1), i.p. or 100 to 600 mg kg(-1), p.o.), 4 h prior, produced significant inhibition of abdominal constrictions caused by i.p. injection of acetic acid, kaolin and zymosan in mice. The mean ID50s were: 21.4, 33.7 and 36.6 mg kg(-1); 173.0, 123.0 and 366.0 mg kg(-1), by i.p. and by oral route, respectively. This effect lasted for up to 8 h. The HE at the same range of doses produced dose-related inhibition of both phases of the formalin-induced licking. The calculated mean ID50s values for the early phase were: 26.1 and 43.0 mg kg(-1), while for the late phase they were 7.3 and 72.7 mg kg(-1), respectively, when given by i.p. and by oral route. The HE (10 to 60 mg kg(-1), i.p. or 25 to 200 mg kg(-1), p.o.), 4 h prior, produced significant inhibition of capsaicin-induced neurogenic pain with mean ID50 values of 18.0 and 68.0 mg kg(-1), respectively. The HE (3 to 100 mg kg(-1), p.o., 1 h) inhibited in a graded manner, the hyperalgesia induced by bradykinin (3 nmol/paw) or substance P (10 nmol/paw) in rat paw, with mean ED50 values of 54.5 and 53.7 mg kg(-1), respectively. However, the HE did not affect the hyperalgesia induced by carrageenan or PGE2. When assessed in the hot-plate test, the HE (200 mg kg(-1), p.o.) was inactive. Naloxone (1 mg kg(-1), i.p.) significantly reversed the antinociceptive effects caused by either morphine (5 mg kg(-1), s.c.) or by HE (60 mg kg(-1), i.p.). Polygodial (0.1 to 10 mg kg(-1), i.p.) produced significant inhibition of acetic acid, kaolin and zymosan-induced writhing in mice, being about 14 to 27-fold more potent than the HE at the ID50 level. Together these data provide support for a long-lasting anti-hyperalgesic property for the active principle(s) present in the barks of D. winteri when assessed in several models of inflammatory or neurogenic pain. Its actions involve, at least in part, an interaction with opioid pathway through a naloxone-sensitive mechanism, seeming not to be related with a non-specific peripheral or central depressant actions. Finally, the sesquiterpene polygodial isolated from this plant, appears to be mainly responsible for the anti-hyperalgesic properties of the extract.
Assuntos
Hiperalgesia/prevenção & controle , Extratos Vegetais/farmacologia , Plantas Medicinais , Sesquiterpenos/farmacologia , Dor Abdominal/induzido quimicamente , Dor Abdominal/tratamento farmacológico , Ácido Acético/toxicidade , Animais , Bradicinina/toxicidade , Capsaicina/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Formaldeído/toxicidade , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar , Sesquiterpenos/isolamento & purificação , Substância P/toxicidade , Zimosan/toxicidadeRESUMO
1 The characterization of the B1 kinin receptor, and some mediators involved in the inflammatory response elicited by intrathoracic (i.t.) administration of des-Arg9-bradykinin (BK) in the mouse model of pleurisy, was investigated. 2 An i.t. injection of des-Arg9-BK (10-100 nmol per site), a selective B1 agonist, caused a significant and dose-related increase in the vascular permeability observed after 5 min, which peaked at 1 h, associated with an increase in cell influx, mainly neutrophils, and, to a lesser extent, mononuclear cell influx, peaking at 4 h and lasting for up to 48 h. The increase in fluid leakage caused by des-Arg9-BK was completely resolved 4 h after peptide injection. I.t. injection of Lys-des-Arg9-BK (30 nmol per site) caused a similar inflammatory response. 3 Both the exudation and the neutrophil influx elicited by i.t. injection of des-Arg9-BK were significantly antagonized (P<0.01) by an i.t. injection of the selective B1 antagonists des-Arg9-[Leu8]-BK (60 and 100 nmol per site) or des-Arg9-NPC 17731 (5 nmol per site), administered in association with des-Arg9-BK (P<0.01), or 30 and 60 min before the cellular peak, respectively. In contrast, an i.t. injection of the B2 bradykinin selective receptor antagonist Hoe 140 (30 nmol per site), at a dose which consistently antagonized bradykinin (10 nmol per site)-induced pleurisy, had no significant effect on des-Arg9-BK-induced pleurisy. 4 An i.t. injection of the selective tachykinin receptor antagonists (NK1) FK 888 (1 nmol per site), (NK2) SR 48968 (20 nmol per site) or (NK3) SR 142801 (10 nmol per site), administered 5 min before pleurisy induction, significantly antagonized neutrophil migration caused by i.t. injection of des-Arg9-BK. In addition, FK 888 and SR 142801, but not SR 48968, also prevented the influx of mononuclear cells in response to i.t. injection of des-Arg9-BK (P<0.01). However, the NK3 receptor antagonist SR 142801 (10 nmol per site) also significantly inhibited des-Arg9-BK-induced plasma extravasation. An i.t. injection of the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP8-37 (1 nmol per site), administered 5 min before pleurisy induction, inhibited des-Arg9-BK-induced plasma extravasation (P<0.01), without significantly affecting the total and differential cell migration. 5 The nitric oxide synthase inhibitors L-NOARG and L-NAME (1 pmol per site), administered 30 min beforehand, almost completely prevented des-Arg9-BK (i.t.)-induced neutrophil cell migration (P<0.01), and, to a lesser extent, mononuclear cell migration (P<0.01). The D-enantiomer D-NAME had no effect on des-Arg9-BK-induced pleurisy. At the same dose range, L-NOARG and L-NAME inhibited the total cell migration (P<0.01). L-NAME, but not L-NOARG caused significant inhibition of des-Arg9-BK-induced fluid leakage. Indomethacin (1 mg kg(-1), i.p.), administered 1 h before des-Arg9-BK (30 nmol per site), inhibited the mononuclear cell migration (P<0.05), but, surprisingly, increased the neutrophil migration at 4 h without interfering with plasma extravasation. The administration of terfenadine (50 mg kg(-1), i.p.), 30 min before des-Arg9-BK (30 nmol per site), did not interfere significantly with the total cell migration or with the plasma extravasation in the mouse pleurisy caused by i.t. injection of des-Arg9-BK. 6 Pretreatment of animals with the lipopolysaccharide of E. coli (LPS; 10 microg per animal, i.v.) for 24 h did not result in any significant change of the inflammatory response induced by i.t. injection of des-Arg9-BK compared with the saline treated group. However, the identical treatment of mice with LPS resulted in a marked enhancement of des-Arg9-BK induced paw oedema (P<0.01). 7 In conclusion, we have demonstrated that the inflammatory response induced by i.t. injection of desArg9-BK, in a murine model of pleurisy, is mediated by stimulation of constitutive B1 receptors. (These responses are largely mediated by release of neuropeptides such as substanceP or CGRP and also by NO, but products derived from cyclo-oxygenase pathway and histamine seem not to be involved. Therefore, these results further support the notion that the B1 kinin receptor has an important role in modulating inflammatory responses, and it is suggested that selective B1 antagonists may provide therapeutic benefit in the treatment of inflammatory and allergic conditions.
Assuntos
Bradicinina/análogos & derivados , Cininas/antagonistas & inibidores , Pleurisia/induzido quimicamente , Pleurisia/patologia , Receptores da Bradicinina/fisiologia , Receptores de Taquicininas/fisiologia , Animais , Bradicinina/toxicidade , Antagonistas dos Receptores da Bradicinina , Permeabilidade Capilar/efeitos dos fármacos , Ciclo Celular , Modelos Animais de Doenças , Edema/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Calidina/análogos & derivados , Calidina/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Neuropeptídeos/fisiologia , Óxido Nítrico/fisiologia , Pleura/citologia , Pleurisia/tratamento farmacológico , Receptores da Bradicinina/agonistas , Receptores de Taquicininas/antagonistas & inibidoresRESUMO
The participation of B1 and B2 types of bradykinin receptors was studied in the rat knee-joint incapacitation test. Five intra-articular successive hourly administrations of bradykinin produced progressive incapacitation, thus indicating that bradykinin induced sensitization to its own nociceptive effect. Four co-injections of bradykinin with the bradykinin B1 receptor antagonist des-Arg9-[Leu8]bradykinin were without nociceptive effect. However, a 5th injection of bradykinin alone produced intense incapacitation. The bradykinin B2 receptor antagonist HOE-140 ([D-Arg)[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), or indomethacin, prevented the bradykinin-induced incapacitation. However, successive co-injections of bradykinin with prostaglandin E2, in contrast to bradykinin alone, did induce incapacitation in animals pretreated with indomethacin or HOE-140. The injection of the bradykinin B1 receptor agonist des-Arg9-bradykinin into prostaglandin E2-treated joints did induce incapacitation, although administration of the bradykinin B1 receptor agonist or prostaglandin E2 alone did not induce incapacitation. In conclusion, in ongoing articular inflammation, it is suggested that the bradykinin B1 receptor is particularly involved with nociceptor activation, while the bradykinin B2 receptor is related to nociceptor sensitization.
Assuntos
Artrite/induzido quimicamente , Bradicinina/toxicidade , Hiperalgesia/induzido quimicamente , Nociceptores/efeitos dos fármacos , Receptores da Bradicinina/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite/patologia , Comportamento Animal/efeitos dos fármacos , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Antagonistas dos Receptores da Bradicinina , Dinoprostona/farmacologia , Membro Posterior/patologia , Indometacina/farmacologia , Articulações/patologia , Masculino , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores da Bradicinina/agonistasRESUMO
1. The effect of interleukin-10 (IL-10) upon the hyperalgesic activities in rats of bradykinin, tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E2 (PGE2) and carrageenin were investigated in a model of mechanical hyperalgesia. 2. Hyperalgesic responses to bradykinin (1 micrograms) were inhibited in a dose-dependent manner by prior treatment with IL-10 (1-100 ng). 3. Hyperalgesic responses to TNF alpha (2.5 pg), IL-1 beta (0.5 pg) and IL-6 (1.0 ng) but not to IL-8 (0.1 ng) and PGE2 (50 ng and 100 ng) were inhibited by prior treatment with IL-10 (10 ng). 4. Hyperalgesic responses to carrageenin (100 micrograms) were inhibited by IL-10 (10 ng) when this cytokine was injected before but not after the carrageenin. 5. A monoclonal antibody to mouse IL-10 potentiated the hyperalgesic responses to carrageenin (10 micrograms) and TNF alpha (0.025 pg) but not that to IL-8 (0.01 ng). 6. In in vitro experiments in human peripheral blood mononuclear cells (MNCs), IL-10 (0.25-4.0 ng ml-1) inhibited in a dose-dependent manner PGE2 production by MNCs stimulated with IL-1 beta (1-64 ng ml-1) or endotoxin (lipopolysaccharide, LPS, 1 iu = 143 pg ml-1) but evoked only small increases in IL-1ra production. 7. These data suggest that IL-10 limits the inflammatory hyperalgesia evoked by carrageenin and bradykinin by two mechanisms: inhibition of cytokine production and inhibition of IL-1 beta evoked PGE2 production. Our data suggest that the latter effect is not mediated via IL-10 induced IL-Ira and may result from suppression by IL-10 of prostaglandin H synthase-2 (COX-2).