RESUMO
Intracerebroventricular (i.c.v.) or intraperitoneal (IP) administration of saredutant (SR48968), an NK2 receptor antagonist, produces anxiolytic-like effects in rodents in a number of animal models of anxiety. NK2 binding sites are present in several limbic structures in rats, including the hippocampus, thalamus, septum and prefrontal cortex, suggesting involvement in the modulation of emotional processes. The current study investigated the behavioral effects of saredutant infused into the ventral hippocampus (VH), a structure associated with cognitive and emotional processes, to clarify the neural substrate underlying the anxiolytic-like effect of the compound. Saredutant (10, 100 or 500 pmol/0.2 µL) was injected bilaterally into the VH of male CD-1 mice tested in the elevated plus-maze and mouse defense test battery (MDTB). Results from the EPM showed that microinjections of 10 pmol/0.2 µL of saredutant increased entries and time spent in the open arms and enhanced end-arm exploration. In the MDTB, saredutant (500 pmol/0.2 µL) decreased vocalizations and increased escape attempts in mice confronted with a rat. Taken together, these results suggest that hippocampal tachykinin mechanisms are involved in the modulation of anxiety and defensive behaviors.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/psicologia , Benzamidas/farmacologia , Hipocampo/fisiologia , Piperidinas/farmacologia , Receptores da Neurocinina-2/antagonistas & inibidores , Animais , Ansiolíticos/administração & dosagem , Aprendizagem da Esquiva/efeitos dos fármacos , Benzamidas/administração & dosagem , Gatos , Reação de Fuga/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/anatomia & histologia , Masculino , Camundongos , Microinjeções , Odorantes , Piperidinas/administração & dosagem , Ratos , Ratos Long-Evans , Técnicas EstereotáxicasRESUMO
Substance P (SP) and its preferred NK1 receptor are widely expressed throughout the fear-processing pathways of the brain and its role in the modulation of experimental anxiety has been demonstrated. SP, like other peptides, are cleaved by peptidases in two fragments: C-terminal (SP 6-11) and N-terminal (SP 1-7) that could be responsible for its anxiogenic-like response. In this study we investigate the effects of i.c.v. micro-injections of SP free acid (SPfa), which is resistant to enzymatic cleavage, the influence of the pretreatment with peptidase inhibitors (PIs), thiorphan and/or phosphoramidon, as well as the effects of SP 6-11 and SP 1-7 and the participation of NK1 and NK2 receptors on their behavioral effects. Adult male Wistar rats were treated with 10 pmol solutions of SP 6-11, SP 1-7 or 1 and 10 pmol of SPfa and evaluated in the elevated plus maze (EPM) test. Other experimental groups received thiorphan 0.2 pmol, phosphoramidon 2 pmol or both PIs 30 min prior SP 1-11, 10 pmol i.c.v. The C-terminal fragment (SP 6-11, 10 pmol) and SPfa (1 pmol) promoted an anxiogenic-like profile of action similar to 10 pmol of SP 1-11, i.e., a decrease of entries and time spent on the open arms, whereas the N-terminal fragment (SP 1-7) was inactive at the EPM. The effect of SP 6-11 was inhibited by pretreatment (100 pmol) with NK1 (FK 888) and NK2 (SR 48968) antagonists. Moreover, both PIs enhanced the SP effect when used alone, but their combination produced an apparent reversion of anxiogenic-like effect produced by SP. Altogether, our results give further support to the SP role in the modulation of experimental anxiety in rats.
Assuntos
Aprendizagem em Labirinto/efeitos dos fármacos , Substância P/análogos & derivados , Substância P/farmacologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Dipeptídeos/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Glicopeptídeos/farmacologia , Indóis/farmacologia , Injeções Intraventriculares , Masculino , Microinjeções/métodos , Atividade Motora/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1 , Fragmentos de Peptídeos/farmacologia , Piperidinas/farmacologia , Inibidores de Proteases , Ácido Pirrolidonocarboxílico/análogos & derivados , Ratos , Ratos Wistar , Receptores da Neurocinina-2/antagonistas & inibidores , Tiorfano/farmacologia , Fatores de TempoRESUMO
The aim of this work was to verify whether formalin would induce leukocyte recruitment following intraperitoneal (i.p.) injection in rats. Formalin (1.25 - 2.5%) induced cell recruitment, which was concentration- and time-dependent (0 - 24 h). Two peaks of leukocyte recruitment were observed. The first peak (from 2 to 4 h) was characterized by a mixed polymorphonuclear and lymphocyte cell population (representing an increase of 100 - 220% and 55 - 60%, respectively), whereas the second peak was characterized by a marked increase in lymphocytes at 24 h (representing an increase of 230%). Pretreatment of animals with specific antagonists for neurokinin NK(1), NK(2), and NK(3) receptors (SR140333, SR48968, and SR142801 compounds, respectively) reduced the early leukocyte increase (representing a significant reduction of 65%, 51%, and 46%, respectively), whereas only the treatment with NK(2)-specific antagonist reduced the late cell increase induced by formalin injection (amounting to a significant reduction of 48%). These results suggested that substance P, neurokinin A, and neurokinin B release accounted for formalin-induced cell migratory activity. The anti-inflammatory drug dexamethasone also reduced cell recruitment, which was mainly related to a reduction in 79% of the neutrophils at 4 h following 1.25% formalin injection, suggesting also a release of lipid mediators (eicosanoids and/or platelet-activating factor) and/or cytokines/chemokines by the formalin injection.
Assuntos
Formaldeído/administração & dosagem , Formaldeído/farmacologia , Leucócitos/fisiologia , Cavidade Peritoneal/fisiologia , Receptores de Taquicininas/antagonistas & inibidores , Animais , Benzamidas/farmacologia , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Injeções Intraperitoneais , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Modelos Biológicos , Neurocinina A/metabolismo , Neurocinina B/metabolismo , Antagonistas dos Receptores de Neurocinina-1 , Lavagem Peritoneal , Piperidinas/farmacologia , Quinuclidinas/farmacologia , Ratos , Ratos Endogâmicos , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-2/efeitos dos fármacos , Receptores da Neurocinina-3/antagonistas & inibidores , Receptores da Neurocinina-3/efeitos dos fármacos , Receptores de Taquicininas/efeitos dos fármacos , Substância P/metabolismo , Fatores de TempoRESUMO
Tachykinins are a family of bioactive peptides that interact with three subtypes of receptors: NK1, NK2 and NK3. Substance P has greater affinity for NK1, and neurokinin A (NKA) for NK2 receptor subtype. Although only NK1 receptor has been characterized in the anterior pituitary gland, some evidence suggests the existence of NK2 receptors in this gland. Therefore, we investigated the presence of NK2 receptors in the anterior pituitary gland of male rats by radioligand binding studies using labeled SR48968, a non peptidic specific antagonist. [3H]SR48968 specific binding to cultured anterior pituitary cells was time-dependent and saturable, but with a lower affinity than previously reported values for cells expressing NK2 receptors. Unlabeled NKA inhibited only partially [(3)H]SR48968 specific binding to whole anterior pituitary cells. Since SR48968 is a non polar molecule, we performed experiments to discriminate surface from intracellular binding sites. SR48968 exhibited both surface and intracellular specific binding. Analysis of the surface-bound ligand indicated that [3H]SR48968 binds to one class of receptor with high affinity. Neurokinin A completely displaced [3H]SR48968 surface specific binding fitting to a two-site/two-state model with high and low affinity. Additionally, immunocytochemical studies showed that the NK2 receptor is expressed at least in a subset of lactotropes. These results demonstrate the presence of NK2 receptors in the anterior pituitary gland and suggest that NKA actions in this gland are mediated, at least in part, by the NK2 receptor subtype.
Assuntos
Adeno-Hipófise/metabolismo , Receptores da Neurocinina-2/biossíntese , Animais , Benzamidas/farmacologia , Sítios de Ligação , Células Cultivadas , Técnicas In Vitro , Masculino , Neurocinina A/farmacologia , Piperidinas/farmacologia , Adeno-Hipófise/citologia , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores da Neurocinina-2/antagonistas & inibidoresRESUMO
We have reported previously that bradykinin (BK) induces potent and reproducible concentration-dependent contractions of the pig iris sphincter (PIS) muscle in vitro through the activation of BK B(2) receptors. Here we attempted to investigate additional mechanisms by which BK induces contraction of the PIS in vitro. BK-mediated contraction of the PIS relied largely on the external Ca2+ influx by a mechanism sensitive to the L-, N- and P-type of Ca2+ channel selective blockers. Likewise, BK-induced contraction of the PIS was greatly inhibited by the CGRP-(8-37), NK(2) or NK(3) receptor antagonists (SR 48968, SR 142801), and to a lesser extent by the NK(1) antagonist (FK 888). Capsaicin desensitization of PIS or capsazepine pre-incubation also significantly reduced BK-mediated contraction in the PIS. Furthermore, KT 5720 or GF 109203X (the protein kinase A and C inhibitors, respectively) also significantly inhibited BK-mediated contraction. Taken together, these results indicate that BK-mediated contraction of the PIS seems to be mediated primarily by the release of CGRP and tachykinins from sensory nerve fibers, and relies largely on extracellular Ca2+ influx via activation of L-, N- and P-type of Ca2+ channels. Finally, these responses are mediated by activation of both protein kinase A- and C-dependent mechanisms.
Assuntos
Bradicinina/farmacologia , Capsaicina/análogos & derivados , Iris/fisiologia , Contração Muscular/efeitos dos fármacos , Animais , Benzamidas/farmacologia , Bradicinina/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Cálcio/metabolismo , Cálcio/farmacologia , Canais de Cálcio/fisiologia , Capsaicina/farmacologia , Carbazóis/farmacologia , Conotoxinas/farmacologia , Dipeptídeos/farmacologia , Relação Dose-Resposta a Droga , Ácido Egtázico/farmacologia , Técnicas In Vitro , Indóis/farmacologia , Iris/efeitos dos fármacos , Maleimidas/farmacologia , Nicardipino/farmacologia , Fragmentos de Peptídeos/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases , Proteínas Quinases/metabolismo , Pirróis/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Receptores de Droga/antagonistas & inibidores , Receptores de Droga/fisiologia , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-2/fisiologia , Receptores da Neurocinina-3/antagonistas & inibidores , Receptores da Neurocinina-3/fisiologia , Suínos , Taquicininas/fisiologia , ômega-Agatoxina IVA/farmacologiaRESUMO
OBJECTIVE: This study examines the pro-inflammatory action caused by subcutaneous (s.c.) injection of the bee venom (BV) Apis melifera in the rat paw. METHODS: Male Wistar rats were used. The venom of Apis melifera was injected s.c. into the rat paw and the oedema formation and the activity of myeleperoxidase (MPO) were measured. RESULTS: Subcutaneous injection of BV caused dose-and time-dependent paw oedema (ED50 of 1.5 microg/paw) with peak at 30 min. The MPO activity increased about 1.6, 4.2 and 8.9 folds at 0.5, 4 and 6 h after s.c. injection of BV. The mast cell degranulating drug 48/80, pyrilamine or metysergide, inhibited BV-mediated oedema formation (88, 62 and 96%, respectively). Likewise, L-NAME, the NK1 antagonist FK 888, the B1 des-Arg9-[Leu8]-BK or B2 kinin antagonist Hoe 140 also antagonised the paw oedema induced by BV (60, 59, 49, and 49%, respectively). SR48968 and SR14280, respectively NK2 and NK3 antagonists and also indomethacin, inhibited by 31, 29 and 22%, respectively BV-induced oedema formation. In contrast, the PAF antagonist WEB 2086 or valeryl salycilate, did not affect the BV-induced paw oedema. The levels of MPO were inhibited by compound 48/80, cyproheptadine, Hoe 140, or by des-Arg9[Leu8]-BK (85, 61, 59, and 53%, respectively) measured 6 h after. CONCLUSION: These results indicate that the BV from Apis melifera causes a marked dose-and time-dependent oedema formation in the rat paw, an effect that is accompanied by intense leukocyte migration. The pro-inflammatory response induced by BV is mediated by several mechanisms, namely the release of histamine and/or serotonin from mast cells, activation of H1 histamine receptor, production of nitric oxide, the involvement of kinins through the activation of B1 and B2 receptors, and also tachykinins acting at NK1 receptor or and to a lesser extent at NK2 and NK3 receptors.
Assuntos
Venenos de Abelha/farmacologia , Pé/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Venenos de Abelha/administração & dosagem , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/patologia , Edema/prevenção & controle , Inibidores Enzimáticos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Indicadores e Reagentes , Injeções Subcutâneas , Masculino , Antagonistas dos Receptores de Neurocinina-1 , Óxido Nítrico Sintase/antagonistas & inibidores , Peroxidase/metabolismo , Ratos , Ratos Wistar , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-3/antagonistas & inibidores , Fatores de TempoRESUMO
This study sought to establish whether sensory neuropeptides and the capsaicin-sensitive fibres are involved in the nociception and oedema formation caused by intraplantar (i.pl.) injection of glutamate into the mouse paw. The i.pl. co-injection of the selective neurokinin (NK) NK(2) (SR 48968, 0.05-0.5 nmol/paw), and to a lesser extent the selective NK(1) (FK 888, 0.25-1.0 nmol/paw) receptor antagonists, resulted in a significant inhibition of glutamate-induced nociception. The percentages of inhibition were 82 and 37%, respectively. In contrast, the selective NK(3) receptor antagonist (SR 142801, 0.25-1.0 nmol/paw) failed to significantly affect glutamate-induced nociception. SR 48968, but not FK 888 or SR 142801, significantly inhibited (36%) glutamate-induced paw oedema formation. The i.pl. injection of kinin B(1) receptor antagonist des-Arg(9)-[Leu(8)]-BK (0.2-0.8 nmol/paw), but not the B(2) receptor antagonist HOE 140 (1.0-4.0 nmol/paw), together with glutamate, also inhibited glutamate-induced nociception (53%) in a graded manner, without affecting glutamate-induced paw oedema. The i.pl. co-injection of the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37) (1 nmol/paw) failed to significantly inhibit glutamate-induced nociception or oedema. Finally, neonatal-capsaicin (50 mg/kg, s.c.) treatment inhibited glutamate-induced nociception by 69% and to a lesser extent glutamate-mediated oedema formation (30%). Collectively, the current results indicate that the nociception caused by i.pl. injection of glutamate in mice is clearly mediated by capsaicin-sensitive fibres and by release of neurokinins from sensory neurones that activate NK(2) receptors and to a lesser extent NK(1) receptors. Furthermore, kinins acting at B(1) (but not at B(2)) receptors also largely account for glutamate-mediated nociceptive behaviour response. In contrast, glutamate-induced paw oedema seems to be primarily mediated via activation of NK(2) receptors and stimulation of capsaicin-sensitive C-fibres. CGRP receptors do not seem to be involved in either of the glutamate responses.
Assuntos
Edema/fisiopatologia , Ácido Glutâmico/farmacologia , Fibras Nervosas/fisiologia , Nociceptores/fisiologia , Dor/fisiopatologia , Animais , Benzamidas/farmacologia , Antagonistas dos Receptores da Bradicinina , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/metabolismo , Capsaicina/farmacologia , Dipeptídeos/farmacologia , Edema/induzido quimicamente , Pé/fisiopatologia , Indóis/farmacologia , Masculino , Camundongos , Fibras Nervosas/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1 , Nociceptores/efeitos dos fármacos , Piperidinas/farmacologia , Receptor B1 da Bradicinina , Receptor B2 da Bradicinina , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-2/efeitos dos fármacos , Receptores da Neurocinina-2/metabolismoRESUMO
The authors assessed the role of substance P (SP) and neurokinin A (NKA) and their receptor antagonists (RAs) SR140333 and SR48968 (respectively for NK(1) and NK(2) receptors) in pulmonary eosinophil influx induced by stimulation of capsaicin (CAP)-sensitive nerve terminals. The increase in respiratory system resistance after capsaicin infusion was attenuated by NK(2)RA and association of NK(1)NK(2)RA (P<.001). Respiratory system elastance (Ers) increase was attenuated with use of NK(1)NK(2)RA (P<.001). In alveolar wall, there was an increase in eosinophils after 30 minutes of CAP infusion (P<.001) and was attenuated after 24 hours. Pretreatment with NK(1)RA, NK(2)RA, and NK(1)NK(2)RA decreased eosinophils in alveolar wall (P<.001). SP induced an increase of eosinophils in alveolar wall (P<.001), although NKA may also contribute to this response. In airway wall, the authors observed an increase of eosinophils at 30 minutes (P=.006) till 24 hours after CAP infusion. They noticed a predominant influx of cells around airway wall after CAP and SP infusion. Pretreatment with NK(1)RA and NK(1)NK(2)RA reduced eosinophils (P<.001) in airway wall. Both SP and NKA contribute to eosinophil lung recruitment in distal airways and in alveolar wall, and these findings suggest that neurokinins may contribute to the development of eosinophilic inflammation in both allergic asthma and hypersensitivity pneumonitis.
Assuntos
Eosinófilos/citologia , Neurocinina A/farmacologia , Pneumonia/imunologia , Alvéolos Pulmonares/imunologia , Substância P/farmacologia , Animais , Benzamidas/farmacologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Cobaias , Masculino , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Alvéolos Pulmonares/citologia , Quinuclidinas/farmacologia , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-2/metabolismoRESUMO
1. The contribution of sensory neurons and mast cells to the oedema evoked by adenosine A1 (N(6)-cyclopentyladenosine, CPA, 3 - 30 nmol site(-1)), A2 (5'N-ethylcarboxamidoadenosine, NECA, 1 - 10 nmol site(-1)) and A3 receptor agonists (N6-[3-iodobenzyl]-N-methyl-5'-carboxiamidoadenosine, IB-MECA, 0.01 - 3 nmol site(-1)) was investigated in the rat skin microvasculature, by the extravascular accumulation of intravenously-injected (i.v.) 125I-albumin. 2. Intradermal (i.d.) injection of adenosine and analogues induced increased microvascular permeability in a dose-dependent manner (IB-MECA > NECA > CPA > adenosine). The non-selective adenosine receptor antagonist theophylline (5 - 50 nmol site(-1)) markedly inhibited adenosine, CPA or NECA but not IB-MECA-induced plasma extravasation. The A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.3 - 3 micromol kg(-1), i.v.) significantly reduced CPA-induced plasma extravasation whereas responses to adenosine, NECA or IB-MECA were unchanged. The A2 receptor antagonist 3,7-dymethyl-1-proprargylxanthine (DMPX, 0.5 - 50 nmol site(-1)) significantly reduced NECA-induced plasma extravasation without affecting responses to adenosine, CPA and IB-MECA. 3. The tachykinin NK1 receptor antagonist (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane chloride (SR140333), but not the NK2 receptor antagonist (S)-N-methyl-N[4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]-benzamide (SR48968), significantly inhibited the plasma extravasation evoked by higher doses of adenosine (100 nmol site(-1)), CPA (100 nmol site(-1)), NECA (1 nmol site(-1)) and IB-MECA (0.1 - 1 nmol site(-1)). In rats treated with capsaicin to destroy sensory neurons, the response to higher doses of adenosine, CPA and NECA, but not IB-MECA, was significantly inhibited. 4. The effects of adenosine and analogues were largely inhibited by histamine and 5-hydroxytryptamine (5-HT) antagonists and by compound 48/80 pretreatment. 5. In conclusion, our results provide evidence that adenosine A1 and A2, but not A3, receptor agonists may function as cutaneous neurogenic pro-inflammatory mediators; acting via microvascular permeability-increasing mechanisms that can, depending on dose of agonist and purine receptor under study, involve the tachykinin NK1 receptor and mast cell amines.
Assuntos
Adenosina/análogos & derivados , Adenosina/farmacologia , Proteínas Sanguíneas/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Pele/efeitos dos fármacos , Adenosina-5'-(N-etilcarboxamida)/farmacologia , Animais , Proteínas Sanguíneas/metabolismo , Capsaicina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Injeções Intradérmicas , Soluções Isotônicas/farmacologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Antagonistas dos Receptores de Neurocinina-1 , Neurônios Aferentes/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Piperidinas/farmacologia , Agonistas do Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Quinuclidinas/farmacologia , Ratos , Ratos Wistar , Receptores da Neurocinina-2/antagonistas & inibidores , Pele/irrigação sanguínea , Pele/metabolismo , Substância P/análogos & derivados , Substância P/farmacologia , Teobromina/análogos & derivados , Teobromina/farmacologia , p-Metoxi-N-metilfenetilamina/farmacologiaRESUMO
OBJECTIVE AND DESIGN: To examine the role of macrophages in the neutrophil migration induced by staphylococcal enterotoxin type A (SEA) in mice. MATERIALS AND METHODS: Peritoneal macrophages were harvested from male Swiss mice pre-treated with thioglycollate. After adhering to plastic tissue culture dishes, the cells were washed and incubated with RPMI or SEA (0.62-2.5 microg/ml) and washed again prior to further incubation with RPMI alone. The medium was then collected, sterilized and assayed for promigratory activity in the mouse peritoneal cavity. RESULTS: Mouse macrophage monolayers stimulated with SEA secreted a thermolabile neutrophil chemotactic component (MNCC-SEA) with a molecular mass >100 kDa (by ultrafiltration). This release was dose- and time-dependent and was inhibited by dexamethasone but not by indomethacin or BW755C. Dexamethasone, indomethacin, BWA4C, BW755C, BN52021, cimetidine and SR48968 had no effect on the neutrophil migration induced by MNCC-SEA while capsaicin and SR 140333 reduced this phenomenon. CONCLUSIONS: Macrophages play a key role in the neutrophil recruitment induced by SEA probably by releasing an MNCC-SEA that presumably induces neutrophil migration via a mechanism mediated by substance P.
Assuntos
Fatores Quimiotáticos/metabolismo , Enterotoxinas/farmacologia , Macrófagos Peritoneais/metabolismo , Neutrófilos/fisiologia , 4,5-Di-Hidro-1-(3-(Trifluormetil)Fenil)-1H-Pirazol-3-Amina/farmacologia , Animais , Benzamidas/farmacologia , Cálcio/farmacologia , Capsaicina/farmacologia , Fatores Quimiotáticos/farmacologia , Quimiotaxia de Leucócito , Inibidores de Ciclo-Oxigenase/farmacologia , Dexametasona/farmacologia , Estabilidade de Medicamentos , Glucocorticoides/farmacologia , Glucose/farmacologia , Indometacina/farmacologia , Magnésio/farmacologia , Masculino , Camundongos , Peso Molecular , Piperidinas/farmacologia , Receptores da Neurocinina-2/antagonistas & inibidores , Tioglicolatos/farmacologiaRESUMO
Intraplantar injection of staphylococcal enterotoxin B induces long-lasting oedema mediated by both cyclooxygenase and lipoxygenase products as well as by neuropeptides from sensory nerves. This study was undertaken to further clarify the role of peripheral primary afferent sensory nerves in staphylococcal enterotoxin B (25 microg/paw)-induced plasma extravasation and oedema formation. The tachykinin NK(1) receptor antagonist (S)-1-[2-[3-(3, 4-dichlorophenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl]-4-phenyl-1 azoniabicyclo [2.2.2]octane cloride (SR140333; 120 nmol/kg, s.c.+120 nmol/kg, i.v.) significantly inhibited plasma exudation and paw oedema evoked by staphylococcal enterotoxin B. The tachykinin NK(2) receptor antagonist (S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3, 4-dichlorophenyl)butyl]-benzamide (SR48968) had no effect on the staphylococcal enterotoxin B-induced responses. The bradykinin B(2) receptor antagonist D-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)]bradykinin (Hoe 140; 400 nmol/kg, i.v.) significantly reduced staphylococcal enterotoxin B-induced responses. The magnitude of the inhibition observed with Hoe 140 alone was similar to that caused by concomitant treatment of animals with SR140333 and Hoe 140, suggesting that there is a final common pathway. Additionally, SR140333 given alone reduced bradykinin (3 nmol/paw)-induced paw oedema. The vanilloid receptor antagonist N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro-7, 8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine; 100 micromol/kg) significantly reduced staphylococcal enterotoxin B-induced responses. The 5-HT receptor antagonist methysergide (10 mg/kg, i.v.) and the histamine H(1) receptor antagonist mepyramine (10 mg/kg, i.v.) produced a significant reduction in paw oedema whereas plasma exudation was reduced only by methysergide. In diabetic mice, exudation and oedema evoked by staphylococcal enterotoxin B were markedly reduced. Acute administration of insulin (20 UI/kg, s.c., 30 min before) did not restore the increased permeability induced by staphylococcal enterotoxin B. We conclude that plasma exudation and paw oedema in response to staphylococcal enterotoxin B are a consequence of a complex neurogenic response involving direct activation of vanilloid receptors on sensory nerves, release of kinins and subsequent activation of bradykinin B(2) receptors at a prejunctional level, and direct or indirect degranulation of mast cells.
Assuntos
Bradicinina/análogos & derivados , Permeabilidade Capilar/efeitos dos fármacos , Capsaicina/análogos & derivados , Edema/fisiopatologia , Enterotoxinas/farmacologia , Cininas/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Animais , Benzamidas/farmacologia , Bradicinina/farmacologia , Capsaicina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Edema/induzido quimicamente , Edema/metabolismo , Membro Posterior/efeitos dos fármacos , Membro Posterior/patologia , Cininas/metabolismo , Masculino , Mastócitos/citologia , Camundongos , Antagonistas dos Receptores de Neurocinina-1 , Neurônios Aferentes/metabolismo , Piperidinas/farmacologia , Pirilamina/farmacologia , Quinuclidinas/farmacologia , Receptores da Neurocinina-2/antagonistas & inibidoresRESUMO
In the present study we have investigated some of the mechanisms underlying B(1) kinin receptor-induced paw edema formation in rats that had been treated with LPS, paying special attention to the involvement of neurogenic inflammation. Intradermal (i.d.) injection of the B(1) receptor agonist des-Arg(9)-BK (100 nmol/paw) resulted in a marked increase in paw volume in animals pre-treated with LPS (0.40+/-0.06 ml). The co-injection of the selective NK(1) FK888 (1 nmol/paw) or NK(2) SR 48968 (3 nmol/paw) receptor antagonists resulted in a significant inhibition of the edema induced by des-Arg(9)-BK (30+/-4 and 25+/-7%, respectively). The NK(3) SR 142801 (3 nmol/paw) antagonist did not demonstrate any significant effect on B(1) receptor-mediated paw edema. The edema induced by des-Arg(9)-BK was also significantly inhibited (33+/-5%) by the co-injection of the CGRP-receptor antagonist CGRP 8-37 (1 nmol/paw) or by treatment of animals with capsaicin (50 mgkg(-1), s.c., 48 h, prior) (45+/-4%). The pre-treatment of animals with methysergide or with mianserin, 5-HT(1) and 5HT(2) antagonists, respectively (both 10 mgkg(-1), i.p. 30 min), resulted in a significant reduction of the edema mediated by B(1) receptors (23+/-5 and 20+/-3%, respectively). In addition, compound 48/80 (12 microg/paw, 24 h) significantly reduced des-Arg(9)-induced paw edema in rats pre-treated with LPS (23+/-3%), while the treatment of animals with the H(1) receptor antagonist pyrilamine (10 mgkg(-1), i.p., 30 min) failed to affect the edematogenic responses involving B(1) receptors. Finally, the co-injection of NOS inhibitors L-NAME (100 nmol/paw) or 7-NINA (10 nmol/paw) did not affect the rat paw edema caused by des-Arg(9)-BK, whereas they significantly inhibited BK-induced paw edema. Jointly, the results of the present study show that the edematogenic response mediated by the activation of B(1) receptors, in animals pre-treated with LPS, involves the release of tachykinins and CGRP, as well as serotonin, while NO and histamine seem not to be involved. Therefore, these data further support the notion that B(1) receptors have an important role in modulating the inflammatory processes.
Assuntos
Bradicinina/análogos & derivados , Lipopolissacarídeos/imunologia , Receptores da Bradicinina/agonistas , Animais , Benzamidas/administração & dosagem , Benzamidas/metabolismo , Bradicinina/administração & dosagem , Bradicinina/imunologia , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Capsaicina/administração & dosagem , Capsaicina/metabolismo , Edema/induzido quimicamente , Edema/imunologia , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Metisergida/administração & dosagem , Metisergida/metabolismo , Mianserina/administração & dosagem , Mianserina/metabolismo , NG-Nitroarginina Metil Éster/administração & dosagem , NG-Nitroarginina Metil Éster/metabolismo , Antagonistas dos Receptores de Neurocinina-1 , Óxido Nítrico Sintase/antagonistas & inibidores , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/metabolismo , Piperidinas/administração & dosagem , Piperidinas/metabolismo , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Piridinas/administração & dosagem , Piridinas/metabolismo , Pirilamina/administração & dosagem , Pirilamina/metabolismo , Ratos , Ratos Wistar , Receptor B1 da Bradicinina , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-3/antagonistas & inibidores , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/metabolismo , p-Metoxi-N-metilfenetilamina/administração & dosagem , p-Metoxi-N-metilfenetilamina/metabolismoRESUMO
We have previously reported that neurokinin A (NKA), a tachykinin closely related to substance P, increases the release of prolactin (PRL) from the anterior pituitary gland of male rats, but not from pituitaries of ovariectomized (OVX) female rats. In this study, we evaluated the influence of estrogens in the action of NKA on PRL secretion in female rats. NKA stimulated the in vitro release of PRL from pituitary glands of OVX-chronically estrogenized rats, and of proestrus and estrus rats, but had no effect in anterior pituitaries of diestrus rats. In addition, we observed that cultured anterior pituitary cells of OVX rats responded to NKA only when they were incubated for 3 days in the presence of estradiol 10(-9) M. This effect was blocked by L-659,877, an NK-2 receptor antagonist. We also studied the action of NKA on PRL release during lactation. The response of anterior pituitary cells to NKA was variable over this period. The maximal sensitivity to NKA was observed at day 10 of lactation. Furthermore, the blockade of endogenous NKA by the administration of an anti-NKA serum to lactating rats reduced the PRL surge induced by the suckling stimulus. These results show that the responsiveness of the anterior pituitary gland of female rats to NKA is modulated by the endocrine environment, and suggest that NKA may participate in the control of PRL secretion during the estrus cycle and lactation.
Assuntos
Estradiol/farmacologia , Neurocinina A/farmacologia , Adeno-Hipófise/metabolismo , Prolactina/metabolismo , Animais , Técnicas de Cultura de Células , Células Cultivadas , Estro/metabolismo , Feminino , Lactação/metabolismo , Técnicas de Cultura de Órgãos , Ovariectomia , Peptídeos Cíclicos/farmacologia , Adeno-Hipófise/efeitos dos fármacos , Ratos , Receptores da Neurocinina-2/antagonistas & inibidoresRESUMO
The role of NK-1 and NK-2 receptors on the pulmonary response to capsaicin in guinea pigs was evaluated using intravenous infusion of selective nonpeptide antagonists of NK 1 (CP 96345, 300 nmol/kg, and SR 140333, 300 nmol/kg) and NK-2 (SR 48968, 100 nmol/kg) neurokinin receptors. Maximal values of pulmonary dynamic elastance (Edyn) and pulmonary resistance (RL) after capsaicin infusion were significantly lower in the presence of SR 48968 (p < .005). Morphometric analysis of lungs obtained by quick-freezing showed significant attenuation of airway contraction and peribronchiolar edema formation in the presence of NK-2 antagonist (p < .001). When compared to guinea pigs that received only capsaicin, animals that received SR 140333 or CP 96345 showed lower values of Edyn, RL, airway contraction, and peribronchiolar edema, but only the difference in Edyn values was significant. The combination of NK-1 and NK-2 antagonists was not more effective than NK-2 antagonist alone in attenuating capsaicin effects. The results suggest that airway effects of capsaicin are mainly mediated by activation of NK-2 receptors although NK-1 receptors may also play a role.
Assuntos
Capsaicina/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/ultraestrutura , Receptores da Neurocinina-1/fisiologia , Receptores da Neurocinina-2/fisiologia , Traqueia/efeitos dos fármacos , Traqueia/ultraestrutura , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Broncoconstrição/efeitos dos fármacos , Edema/induzido quimicamente , Cobaias , Masculino , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Quinuclidinas/farmacologia , Receptores da Neurocinina-2/antagonistas & inibidoresRESUMO
This study assessed the effects of intracerebroventricular administration of selective agonists and antagonists for tachykinin NK1 and NK2 receptors on performance of mice in the elevated plus-maze, an ethological model of anxiety. Mice were treated with either vehicle (5 microliters) or 1, 10, 100 or 500 pmol of substance P, neurokinin A, the selective NK1 receptor agonist substance P methyl ester, or the selective NK2 receptor agonist, [beta-Ala8]neurokinin A-(4-10). Other mice received similar doses of FK 888, i.e., N2-[(4R)-4-hydroxy-1-(1-methyl-1 H-indol-3-y)carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-L- alaninamide, or SR 48968, i.e., (S)-N-methyl-(N-[4-acetylamine-4-phenylpiperidine)-2-(3, 4-dichlorophenyl)buthyl]benzamide, selective antagonists of tachykinin NK1 and NK2 receptors, respectively. Injections of substance P, neurokinin A, substance P methyl ester or [beta-Ala8]neurokinin A-(4-10) significantly reduced the frequency of open arm entries, and [beta-Ala8]neurokinin A-(4-10) also enhanced the percentage of entries into enclosed arms. Conversely, the NK1 antagonist FK 888 and the NK2 antagonist SR 48968 each increased the time spent in the open arms, and SR 48968 also increased the frequency of entries into the open arms. None of the tachykinin receptor agonists or antagonists modified motor performance and coordination on the rotarod apparatus or ambulation in an activity cage. Together, these results suggest that centrally administered NK1 and NK2 receptor agonists and antagonists can modulate anxiety, as evaluated in the elevated plus-maze test in mice. Stimulation of either tachykinin NK1 or NK2 receptors induces anxiogenic-like responses, whereas the reverse occurs following their blockade. The anxiolytic-like profiles of action of both tachykinin NK1 and NK2 receptor antagonists suggest that central tachykinin mechanisms are tonically involved in the modulation of anxiety.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Receptores de Taquicininas/agonistas , Receptores de Taquicininas/antagonistas & inibidores , Animais , Ansiolíticos/administração & dosagem , Ansiedade/psicologia , Benzamidas/farmacologia , Dipeptídeos/farmacologia , Relação Dose-Resposta a Droga , Indóis/farmacologia , Injeções Intraventriculares , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Neurocinina A/administração & dosagem , Neurocinina A/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Equilíbrio Postural/efeitos dos fármacos , Receptores da Neurocinina-1/agonistas , Receptores da Neurocinina-2/agonistas , Receptores da Neurocinina-2/antagonistas & inibidores , Substância P/administração & dosagem , Substância P/farmacologiaRESUMO
1. The hydroalcoholic extract (HE) of stems, leaves and roots from P. urinaria (Euphorbiaceae) (1-3000 micrograms/ml), caused graded contraction in guinea pig trachea (GPT), being more effective in preparations without epithelium. 2. Response to HE was slightly affected by tetrodotoxin (0.3 microM) and nicardipine (1 microM), but was unaffected by w-conotoxin, atropine, mepyramine or staurosporine (all 1 microM). Indomethacin (3 microM) greatly inhibited HE contraction, but MK 571 (leukotriene D4 and E4 antagonist) caused partial inhibition; L-655,240 (thromboxane A2 antagonist) and WEB 2086 (PAF antagonist) (all 1 microM) were ineffective. 3. Response to HE was markedly inhibited in a Ca(2+)-free solution and was partially affected in GPT desensitized to capsaicin (10 microM). 4. Capsazepine (capsaicin antagonist, 3 microM) antagonized the contraction from capsaicin, leaving the response to HE unaffected. In contrast, ruthenium red (an ionic channel antagonist coupled to vanilloid receptors of capsaicin) (0.1-3 microM) caused graded and equipotent noncompetitive inhibition of HE- and capsaicin-induced contractions, but had no effect on carbachol- and prostaglandin E2-mediated responses. 5. FK 888 and SR 48968 (NK1 and NK2 receptor antagonists, respectively) (both 1 microM) antagonized, through a competitive mechanism, the contraction from SP and [beta-ala8]NKA (4-10) respectively, but antagonized, through a noncompetitive mechanism, HE-mediated contraction. 6. We concluded that contraction to HE in GPT is modulated by the epithelium, depends on the release of a cyclo-oxygenase metabolite, and relies largely upon an extracellular Ca2+ influx that is highly sensitive to ruthenium red, but is insensitive to L and N-type of voltage-sensitive Ca2+ channel antagonists. In addition, NK1 and NK2 tachykinins, but not vanilloid receptors, play an important role in mediating its response.