Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / nÃo hà / Paclitaxel(TaxolÂ), foi o 1 antineoplÃsico efetivo no tratamento de cÃnceres refratÃrios a quimioterapia convencional. Clinicamente, induz mielossupressÃo e neuropatia perifÃrica sensorial dose-limitante e cumulativa, jà bem documentada na literatura. Menos freqÃentemente os pacientes tratados apresentam mialgias e artralgias. No que diz respeito à dor inflamatÃria, nada foi descrito atà o momento, visando correlacionar o envolvimento das citocinas prÃ-inflamatÃrias, com a gÃnese da hiperalgesia associada ao PCX, jà que a droga induz a expressÃo do gene TNF-alpha. Experimentalmente jà foi demonstrado por vÃrios autores, o papel fundamental do TNF-alpha desencadeando uma cascata de citocinas que ativam os dois componentes da dor inflamatÃria (eicosanÃide e simpÃtico). Dados do nosso laboratÃrio registram que o zymosan (ZY) administrado ip em camundongos, induz a liberaÃÃo dessas citocinas por macrÃfagos residentes no modelo de contorÃÃo abdominal (CA), e que sua injeÃÃo intra-articular em joelhos de ratos produz uma periartrite caracterÃstica tida como sinal de hiperalgesia no modelo de incapacitaÃÃo articular (IA). Com base nestes achados, constituiu-se objetivo do presente trabalho, avaliar o efeito do PCX na modulaÃÃo da resposta nociceptiva induzida pelo ZY em dois modelos animais de dor inflamatÃria. Para tanto, injetou-se via ip PCX (8mg/kg/an) 2h antes do ZY (1mg/cav;ip) em camundongos no teste CA. Ratos foram tratados ip com PCX 4 e 8mg/kg/an) 1 h apÃs da administraÃÃo intra-articular ZY (250mcg/an) no teste IA. Em ambos os testes os animais foram prÃ-tratados via Sc com inibidores de COX-1 e COX-2, bloqueador simpÃtico e inibidores de citocinas. Ficou demonstrado que PCX na dose de 8mg/kg potencializa a hiperalgesia inflamatÃria no modelo de CA, aumentando de maneira significativa (p< 0.001) o n de CA em 183%, em relaÃÃo ao controle. Tal efeito foi inibido de maneira significativa (p<0.001) e dose-dependente pela indometacina (ED50 0,05mg/kg), celecoxib (ED50 13,68mg/kg), atenolol (ED50 0,13mg/kg), talidomida (ED50 23,36mg/kg), pentoxifilina (ED50 8,40mg/kg) e dexametasona (ED50 0,71mg/kg). No teste de IA, esse efeito potencializador foi ratificado pelo aumento significativo do tempo de suspensÃo da pata (p< 0.001) na 3 e 4Âh de artrite em relaÃÃo ao controle, na dose 4mg/kg de PCX. Da mesma forma houve inibiÃÃo significativa (p< 0.001) dessa amplificaÃÃo nos ratos prÃ-tratados. Por fim, o PCX (TaxolÂ) amplifica significativamente a hiperalgesia inflamatÃria induzida pelo ZY no modelo de CA e IA, o que justifica em parte as mialgias e artralgias dos pacientes em uso de PCX e indiretamente sugere a participaÃÃo de citocinas hiperalgÃsicas (TNF-alpha), prostanÃides e mediadores simpÃticos na gÃnese deste efeito hipernociceptivo. / Paclitaxel (TaxolÂ) was the first effective antineoplastic in the management of refractory neoplasias to the conventional chemotherapy. It induces clinically to myelosuppression and sensory peripheral neuropathy boundary and cumulative dose, well documented at literature already. Less often the patients exhibited myalgias and arthralgias. As to concern to the inflammatory pain, there is nothing described do date, aiming to correlate the involvement from pro-inflammatory cytokines with the hyperalgesia genesis associated to PCX since the drug induces the alpha-TNF expression gene. It has already been demonstrated, experimentally by several authors, the essential role of alpha-TNF triggering a set of cytokines which active two components of the inflammatory pain (eicosanoid and sympathetic). Findings of our group showed that zymosan (ZY) administrated intraperitoneal (ip) in mice, induces the release of these cytokines by resident macrophages at the wriggling abdominal model (CA) and that their injection intra-articular rat knees produces a feature periarthritis as a sign of hyperalgesia at articular incapacitation model (IA). Based on these findings, the aim of the present work was to evaluate PCX effect at the modulation of nociceptive response induced by zymosan in two animal models of the inflammatory pain. Then, was injected via ip PCX (8mg/kg/an) before two hours of ZY (1mg/cav;ip) in mice on the CA test. Rats were treated with ip PCX (4,8 mg/kg/an) after one hour ZY intra-articular (250mcg/animal;i-art) for IA test. Both tests, the animals were pre-treated subcutaneous via with COX-1 and COX-2 inhibitors, sympathetic blockade and citokines inhibitors. It was demonstrated that PCX (8mg/kg/an) dose potentiates the inflammatory hyperalgesia at CA model, increasing in 183%, being statistical significant at the level p< 0.001, versus experimental group. Such effect was inhibited at level of significance, p< 0.001 and dependent-dose by indomethacin (ED50 0.05mg/kg), celoxib (ED5013.68mg/kg), atenolol(ED50 0.13mg/kg), talidomide (ED50 23.36mg/kg), penthoxyphylin (ED50 8.40mg/kg) and dexamethasone (ED50 0,71mg/kg). This potential effect of at the IA test was justified at IA model in dose 4mg/kg (p< 0,001) by significant increase of time of suspension the paws through arthritis at third and fourth hours versus experimental group. By same way there was significant inhibition at the level p< 0.001 of this magnification of the pre-treated rats. Latter, PCX (TaxolÂ) magnified significantly the inflammatory hyperalgesia induced by ZY at CA and IA models, justifying one sided myalgias and artralgias of the patients by using PCX, suggesting the involvement of the hyperalgesic citokines - alpha-TNF, prostanoids and sympathetic mediators of the genesis of this hyper-nociceptive effect.
| Identifer | oai:union.ndltd.org:IBICT/oai:www.teses.ufc.br:220 |
| Date | 03 October 2003 |
| Creators | Mirlane GuimarÃes de Melo Cardoso |
| Contributors | Ronaldo de Albuquerque Ribeiro, Carlos MaurÃcio de Castro Costa, Francisco Airton Castro da Rocha |
| Publisher | Universidade Federal do CearÃ, Programa de PÃs-GraduaÃÃo em Farmacologia, UFC, BR |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da UFC, instname:Universidade Federal do Ceará, instacron:UFC |
| Rights | info:eu-repo/semantics/openAccess |
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