Envolvimento das cininas na dor do tipo fibromialgia induzida por reserpina e o efeito dos inibidores da enzima conversora de angiotensina I em camundongos
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/20943 |
Resumo: | Fibromyalgia is a chronic disease potentially disabling, characterized by widespread pain and a range of comorbidities as hypertension, besides not having specific pathophysiology or appropriate treatment. Evidence has demonstrated the contribution of kinins and their B1 and B2 receptors in chronic painful conditions. Additionally, the use of angiotensin I converting enzyme (ACE) inhibitor drugs by hypertensive patients has been associated with a potentiation of painful symptoms. Thus, we investigated the involvement of kinin B1 and B2 receptors in the reserpine-induced fibromyalgia-like pain and the effect of ACE inhibitors on this pain. For the induction of fibromyalgia model, male Swiss mice received one subcutaneous injection of reserpine (1 mg/kg, s.c.) once daily for 3 consecutive days. Nociceptive parameters such as mechanical and cold allodynia and spontaneous nociception, besides burrowing, thigmotaxis, forced swimming, and muscle strength test were evaluated at one day after the last reserpine administration. The role of kinin B1 and B2 receptors was investigated using knockout mice or pharmacological antagonism. Additionally, kinin B1 and B2 receptors expression and the bradykinin and monoamines levels were analyzed in the sciatic nerve, spinal cord and cerebral cortex of the animals. The effect of ACE inhibitors was evaluated on nociceptive parameters (mechanical and cold allodynia and spontaneous nociception) in animals previously treated with reserpine and also treated with kinin receptor antagonists. The bradykinin levels, as well as the activity of ACE and kininase I also were measured. Knockout mice for the B1 and B2 kinin receptor prevented the reserpine-induced mechanical allodynia. The antagonism of kinin B1 and B2 receptors also reduced the mechanical allodynia, the cold allodynia, and the spontaneous nociception reserpine-induced. The reserpine altered thigmotaxis, burrowing, forced swimming, and grip strength behavior of the mice. Moreover, reserpine increased the kinin B1 and B2 receptors expression and the kinin levels, as well as, reduced the monoamines levels in peripheral and central structures. The ACE inhibitors enalapril and captopril increased the reserpine-induced mechanical allodynia and this increase was prevented by kinin B1 and B2 receptor antagonists. Submaximal doses of substance P and bradykinin caused spontaneous nociception and increased mechanical allodynia in animals treated with reserpine. The reserpine administration associated with ACE inhibitors increased and bradykinin levels and inhibited the ACE activity in structures involved in the pain modulation. We evidence that kinins and their B1 and B2 receptors are involved in the fibromyalgia-like pain. In addition, we can suggest that therapy with ACE inhibitors in hypertensive patients and with fibromyalgia requires a careful analysis since this could potentiate their painful symptoms. Thus, hypertension treatment in patients with fibromyalgia could include classes of antihypertensive drugs diferents from ACE inhibitors. Our results indicate that kinin receptor antagonists may be promising drugs for relieving the pain of patients with fibromyalgia including those in treatment with ACE inhibitors. |
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Envolvimento das cininas na dor do tipo fibromialgia induzida por reserpina e o efeito dos inibidores da enzima conversora de angiotensina I em camundongosKinins involvement in the reserpine-induced fibromyalgia-like pain and the effect of angiotensin I conversing enzyme inhibitors in miceAlodínia mecânicaAlodínia ao frioNocicepção espontâneaMonoaminasEnalaprilMechanical allodyniaCold allodyniaSpontaneous nociceptionMonoaminesCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAFibromyalgia is a chronic disease potentially disabling, characterized by widespread pain and a range of comorbidities as hypertension, besides not having specific pathophysiology or appropriate treatment. Evidence has demonstrated the contribution of kinins and their B1 and B2 receptors in chronic painful conditions. Additionally, the use of angiotensin I converting enzyme (ACE) inhibitor drugs by hypertensive patients has been associated with a potentiation of painful symptoms. Thus, we investigated the involvement of kinin B1 and B2 receptors in the reserpine-induced fibromyalgia-like pain and the effect of ACE inhibitors on this pain. For the induction of fibromyalgia model, male Swiss mice received one subcutaneous injection of reserpine (1 mg/kg, s.c.) once daily for 3 consecutive days. Nociceptive parameters such as mechanical and cold allodynia and spontaneous nociception, besides burrowing, thigmotaxis, forced swimming, and muscle strength test were evaluated at one day after the last reserpine administration. The role of kinin B1 and B2 receptors was investigated using knockout mice or pharmacological antagonism. Additionally, kinin B1 and B2 receptors expression and the bradykinin and monoamines levels were analyzed in the sciatic nerve, spinal cord and cerebral cortex of the animals. The effect of ACE inhibitors was evaluated on nociceptive parameters (mechanical and cold allodynia and spontaneous nociception) in animals previously treated with reserpine and also treated with kinin receptor antagonists. The bradykinin levels, as well as the activity of ACE and kininase I also were measured. Knockout mice for the B1 and B2 kinin receptor prevented the reserpine-induced mechanical allodynia. The antagonism of kinin B1 and B2 receptors also reduced the mechanical allodynia, the cold allodynia, and the spontaneous nociception reserpine-induced. The reserpine altered thigmotaxis, burrowing, forced swimming, and grip strength behavior of the mice. Moreover, reserpine increased the kinin B1 and B2 receptors expression and the kinin levels, as well as, reduced the monoamines levels in peripheral and central structures. The ACE inhibitors enalapril and captopril increased the reserpine-induced mechanical allodynia and this increase was prevented by kinin B1 and B2 receptor antagonists. Submaximal doses of substance P and bradykinin caused spontaneous nociception and increased mechanical allodynia in animals treated with reserpine. The reserpine administration associated with ACE inhibitors increased and bradykinin levels and inhibited the ACE activity in structures involved in the pain modulation. We evidence that kinins and their B1 and B2 receptors are involved in the fibromyalgia-like pain. In addition, we can suggest that therapy with ACE inhibitors in hypertensive patients and with fibromyalgia requires a careful analysis since this could potentiate their painful symptoms. Thus, hypertension treatment in patients with fibromyalgia could include classes of antihypertensive drugs diferents from ACE inhibitors. Our results indicate that kinin receptor antagonists may be promising drugs for relieving the pain of patients with fibromyalgia including those in treatment with ACE inhibitors.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESA fibromialgia é uma doença crônica potencialmente incapacitante caracterizada por dor generalizada e uma série de comorbidades como a hipertensão, além de não possuir patofisiologia específica ou tratamento apropriado. Evidências têm demonstrado a contribuição das cininas e seus receptores B1 e B2 em condições dolorosas crônicas. Adicionalmente, o uso de drogas inibidoras da enzima conversora de angiotensina I (ECA) por pacientes hipertensos tem sido associado com uma potencialização de sintomas dolorosos. Desta forma, nós investigamos o envolvimento dos receptores B1 e B2 de cininas na dor tipo fibromialgia induzida por reserpina e o efeito dos inibidores da ECA sobre essa dor. Para a indução do modelo de fibromialgia camundongos Swiss machos receberam uma injeção subcutânea de reserpina (1 mg/kg, s.c.) uma vez por dia por 3 dias consecutivos. Parâmetros nociceptivos como alodínia mecânica e ao frio e nocicepção espontânea, além do teste de burrowing, tigmotaxia, nado forçado e força muscular, foram avaliados em um dia após a última administração de reserpina. O papel dos receptores B1 e B2 de cininas foi investigado usando camundongos nocaute ou antagonismo farmacológico. Adicionalmente, a expressão dos receptores de cininas e os níveis de bradicinina e monoaminas foram analisados no nervo ciático, medula espinhal e córtex cerebral dos animais. O efeito dos inibidores da ECA foi avaliado sobre os parâmetros nociceptivos (alodínia mecânica e ao frio e nocicepção espontânea) em animais previamente tratados com reserpina e também tratados com antagonistas dos receptores de cininas. Os níveis de bradicinina, assim como a atividade da ECA e da cininase I também foram mensurados. Camundongos nocaute para o receptor B1 e B2 de cininas preveniram o desenvolvimento de alodínia mecânica induzida por reserpina. O antagonismo desses receptores também reduziu a alodínia mecânica e ao frio e a nocicepção espontânea induzida por reserpina. A reserpina alterou os comportamentos de tigmotaxia, burrowing, nado forçado e força muscular dos camundongos. Além disso, a reserpina aumentou a expressão dos receptores B1 and B2 de cininas e os níveis de bradicinina, assim como reduziu os níveis de monoaminas em estruturas periféricas e centrais. Os inibidores da ECA enalapril e captopril aumentaram a alodínia mecânica induzida por reserpina e esse aumento foi prevenido pelos antagonistas dos receptores B1 e B2 de cininas. Doses submáximas de substância P e bradicinina causaram nocicepção espontânea e aumentaram a alodínia mecânica em animais tratados com reserpina. A administração de reserpina associada com inibidores da ECA aumentou os níveis de bradicinina e inibiu a atividade da ECA em estruturas envolvidas na modulação da dor. Evidenciamos que as cininas e seus receptores B1 e B2 estão envolvidos na dor do tipo fibromialgia. Além disso, podemos sugerir que a terapia com inibidores da ECA em pacientes hipertensos e com fibromialgia requer uma análise cuidadosa, uma vez isso poderia potencializar seus sintomas dolorosos. Logo, o tratamento da hipertensão em pacientes com fibromialgia poderia incluir classes de medicamentos anti-hipertensivos diferentes de inibidores da ECA. Nossos resultados também apontam que antagonistas dos receptores de cininas podem ser promissores para aliviar a dor de pacientes com fibromialgia.Universidade Federal de Santa MariaBrasilBioquímicaUFSMPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaCentro de Ciências Naturais e ExatasOliveira, Sara Marchesan dehttp://lattes.cnpq.br/6574555059806902Piato, Angelo Luis StapassoliRosemberg, Denis BroockAndré, EuniceOliveira, Mauro SchneiderBrusco, Indiara2021-05-20T17:46:50Z2021-05-20T17:46:50Z2019-03-29info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/20943porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2021-05-21T06:03:02Zoai:repositorio.ufsm.br:1/20943Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2021-05-21T06:03:02Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Envolvimento das cininas na dor do tipo fibromialgia induzida por reserpina e o efeito dos inibidores da enzima conversora de angiotensina I em camundongos Kinins involvement in the reserpine-induced fibromyalgia-like pain and the effect of angiotensin I conversing enzyme inhibitors in mice |
title |
Envolvimento das cininas na dor do tipo fibromialgia induzida por reserpina e o efeito dos inibidores da enzima conversora de angiotensina I em camundongos |
spellingShingle |
Envolvimento das cininas na dor do tipo fibromialgia induzida por reserpina e o efeito dos inibidores da enzima conversora de angiotensina I em camundongos Brusco, Indiara Alodínia mecânica Alodínia ao frio Nocicepção espontânea Monoaminas Enalapril Mechanical allodynia Cold allodynia Spontaneous nociception Monoamines CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Envolvimento das cininas na dor do tipo fibromialgia induzida por reserpina e o efeito dos inibidores da enzima conversora de angiotensina I em camundongos |
title_full |
Envolvimento das cininas na dor do tipo fibromialgia induzida por reserpina e o efeito dos inibidores da enzima conversora de angiotensina I em camundongos |
title_fullStr |
Envolvimento das cininas na dor do tipo fibromialgia induzida por reserpina e o efeito dos inibidores da enzima conversora de angiotensina I em camundongos |
title_full_unstemmed |
Envolvimento das cininas na dor do tipo fibromialgia induzida por reserpina e o efeito dos inibidores da enzima conversora de angiotensina I em camundongos |
title_sort |
Envolvimento das cininas na dor do tipo fibromialgia induzida por reserpina e o efeito dos inibidores da enzima conversora de angiotensina I em camundongos |
author |
Brusco, Indiara |
author_facet |
Brusco, Indiara |
author_role |
author |
dc.contributor.none.fl_str_mv |
Oliveira, Sara Marchesan de http://lattes.cnpq.br/6574555059806902 Piato, Angelo Luis Stapassoli Rosemberg, Denis Broock André, Eunice Oliveira, Mauro Schneider |
dc.contributor.author.fl_str_mv |
Brusco, Indiara |
dc.subject.por.fl_str_mv |
Alodínia mecânica Alodínia ao frio Nocicepção espontânea Monoaminas Enalapril Mechanical allodynia Cold allodynia Spontaneous nociception Monoamines CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
topic |
Alodínia mecânica Alodínia ao frio Nocicepção espontânea Monoaminas Enalapril Mechanical allodynia Cold allodynia Spontaneous nociception Monoamines CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
Fibromyalgia is a chronic disease potentially disabling, characterized by widespread pain and a range of comorbidities as hypertension, besides not having specific pathophysiology or appropriate treatment. Evidence has demonstrated the contribution of kinins and their B1 and B2 receptors in chronic painful conditions. Additionally, the use of angiotensin I converting enzyme (ACE) inhibitor drugs by hypertensive patients has been associated with a potentiation of painful symptoms. Thus, we investigated the involvement of kinin B1 and B2 receptors in the reserpine-induced fibromyalgia-like pain and the effect of ACE inhibitors on this pain. For the induction of fibromyalgia model, male Swiss mice received one subcutaneous injection of reserpine (1 mg/kg, s.c.) once daily for 3 consecutive days. Nociceptive parameters such as mechanical and cold allodynia and spontaneous nociception, besides burrowing, thigmotaxis, forced swimming, and muscle strength test were evaluated at one day after the last reserpine administration. The role of kinin B1 and B2 receptors was investigated using knockout mice or pharmacological antagonism. Additionally, kinin B1 and B2 receptors expression and the bradykinin and monoamines levels were analyzed in the sciatic nerve, spinal cord and cerebral cortex of the animals. The effect of ACE inhibitors was evaluated on nociceptive parameters (mechanical and cold allodynia and spontaneous nociception) in animals previously treated with reserpine and also treated with kinin receptor antagonists. The bradykinin levels, as well as the activity of ACE and kininase I also were measured. Knockout mice for the B1 and B2 kinin receptor prevented the reserpine-induced mechanical allodynia. The antagonism of kinin B1 and B2 receptors also reduced the mechanical allodynia, the cold allodynia, and the spontaneous nociception reserpine-induced. The reserpine altered thigmotaxis, burrowing, forced swimming, and grip strength behavior of the mice. Moreover, reserpine increased the kinin B1 and B2 receptors expression and the kinin levels, as well as, reduced the monoamines levels in peripheral and central structures. The ACE inhibitors enalapril and captopril increased the reserpine-induced mechanical allodynia and this increase was prevented by kinin B1 and B2 receptor antagonists. Submaximal doses of substance P and bradykinin caused spontaneous nociception and increased mechanical allodynia in animals treated with reserpine. The reserpine administration associated with ACE inhibitors increased and bradykinin levels and inhibited the ACE activity in structures involved in the pain modulation. We evidence that kinins and their B1 and B2 receptors are involved in the fibromyalgia-like pain. In addition, we can suggest that therapy with ACE inhibitors in hypertensive patients and with fibromyalgia requires a careful analysis since this could potentiate their painful symptoms. Thus, hypertension treatment in patients with fibromyalgia could include classes of antihypertensive drugs diferents from ACE inhibitors. Our results indicate that kinin receptor antagonists may be promising drugs for relieving the pain of patients with fibromyalgia including those in treatment with ACE inhibitors. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-03-29 2021-05-20T17:46:50Z 2021-05-20T17:46:50Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/20943 |
url |
http://repositorio.ufsm.br/handle/1/20943 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Bioquímica UFSM Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica Centro de Ciências Naturais e Exatas |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Bioquímica UFSM Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica Centro de Ciências Naturais e Exatas |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
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1805922074785480704 |