Participação do receptor de potencial transitório anquirina 1 e disfunção mitocondrial em um modelo de fibromialgia em camundongos
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/27134 |
Resumo: | Fibromyalgia is a painful condition associated with several comorbidities. Although the mechanism underlying fibromyalgia remains unknown, monoamine depletion, reactive oxygen species (ROS) overproduction, and mitochondrial dysfunction appear relevant in its pathogenesis. Once Transient Receptor Potential Ankyrin 1 (TRPA1), an oxidative stress sensor, is involved in conditions related to the pathogenesis of fibromyalgia, including spontaneous and musculoskeletal pain, fatigue and depressive and anxiety behaviours, we hypothesized that TRPA1 could be involved with fibromyalgia symptoms. The fibromyalgia model was induced by subcutaneous injections of reserpine (1 mg/kg) once daily for three consecutive days in Swiss and C57BL/6J mice and in TRPA1-deficient mice. All behavioural tests were performed on the 4 th day after the first administration of reserpine. Immediately after, the animals were euthanized, and different tissues (gastrocnemius and soleus muscles, plantar tissue, sciatic nerve, and spinal cord) were collected for biochemical investigations. Coenzyme Q10 and oligomycin were used to assess mitochondrial function and characteristic symptoms of fibromyalgia. α-lipoic acid was used to elucidate the role of oxidative stress in the fibromyalgia model. The TRPA1 antagonist, A-967079, was used to assess TRPA1 involvement, while the pregabalin or duloxetine were used as reference drugs for fibromyalgia symptoms. Reserpine reduced monoamine levels, caused mechanical and cold allodynia, chemical hypersensitivity, reduced muscle strength and burrowing behaviour, caused thigmotaxic behaviour and increased the immobility time of animals in the forced swim test. Oligomycin exacerbated reserpine-induced fibromyalgia-like symptoms, while coenzyme Q10, α-lipoic acid, A-967079, pregabalin, and duloxetine attenuated different reserpine-induced nociceptive and comorbid parameters. Local administration of reserpine induced acute hypersensitivity. Reserpine induced mitochondrial dysfunction (high-resolution respirometry) and altered oxidative status (ROS levels and lipid peroxidation) in the soleus and gastrocnemius muscles and spinal cord. Reserpine increased H2O2 levels in the plantar tissue and increased staining for 4-hydroxynononeal in the sciatic nerve. These oxidative parameters and fibromyalgia-like painful symptoms were not observed when reserpine was administered in TRPA1-deficient mice. Thus, mitochondrial dysfunction and oxidative stress are essential mechanisms for TRPA1 activation and, therefore, for the development and maintenance of the hypersensitivity and some comorbidities observed in this fibromyalgia model. In this way, we contribute to advances in the mechanisms involved in the pathophysiology of fibromyalgia and encourage the use of possible new treatments to control the symptoms of this pathology. |
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Participação do receptor de potencial transitório anquirina 1 e disfunção mitocondrial em um modelo de fibromialgia em camundongosTransient receptor potential ankyrin 1 participation and mitochondrial dysfunction in a mice model of fibromyalgiaDor muscularDor nociplásticaDepressãoRespirometria de alta resoluçãoEstresse oxidativoTRPA1Muscle painNociplastic painDepressionHigh-resolution respirometryOxidative stressCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAFibromyalgia is a painful condition associated with several comorbidities. Although the mechanism underlying fibromyalgia remains unknown, monoamine depletion, reactive oxygen species (ROS) overproduction, and mitochondrial dysfunction appear relevant in its pathogenesis. Once Transient Receptor Potential Ankyrin 1 (TRPA1), an oxidative stress sensor, is involved in conditions related to the pathogenesis of fibromyalgia, including spontaneous and musculoskeletal pain, fatigue and depressive and anxiety behaviours, we hypothesized that TRPA1 could be involved with fibromyalgia symptoms. The fibromyalgia model was induced by subcutaneous injections of reserpine (1 mg/kg) once daily for three consecutive days in Swiss and C57BL/6J mice and in TRPA1-deficient mice. All behavioural tests were performed on the 4 th day after the first administration of reserpine. Immediately after, the animals were euthanized, and different tissues (gastrocnemius and soleus muscles, plantar tissue, sciatic nerve, and spinal cord) were collected for biochemical investigations. Coenzyme Q10 and oligomycin were used to assess mitochondrial function and characteristic symptoms of fibromyalgia. α-lipoic acid was used to elucidate the role of oxidative stress in the fibromyalgia model. The TRPA1 antagonist, A-967079, was used to assess TRPA1 involvement, while the pregabalin or duloxetine were used as reference drugs for fibromyalgia symptoms. Reserpine reduced monoamine levels, caused mechanical and cold allodynia, chemical hypersensitivity, reduced muscle strength and burrowing behaviour, caused thigmotaxic behaviour and increased the immobility time of animals in the forced swim test. Oligomycin exacerbated reserpine-induced fibromyalgia-like symptoms, while coenzyme Q10, α-lipoic acid, A-967079, pregabalin, and duloxetine attenuated different reserpine-induced nociceptive and comorbid parameters. Local administration of reserpine induced acute hypersensitivity. Reserpine induced mitochondrial dysfunction (high-resolution respirometry) and altered oxidative status (ROS levels and lipid peroxidation) in the soleus and gastrocnemius muscles and spinal cord. Reserpine increased H2O2 levels in the plantar tissue and increased staining for 4-hydroxynononeal in the sciatic nerve. These oxidative parameters and fibromyalgia-like painful symptoms were not observed when reserpine was administered in TRPA1-deficient mice. Thus, mitochondrial dysfunction and oxidative stress are essential mechanisms for TRPA1 activation and, therefore, for the development and maintenance of the hypersensitivity and some comorbidities observed in this fibromyalgia model. In this way, we contribute to advances in the mechanisms involved in the pathophysiology of fibromyalgia and encourage the use of possible new treatments to control the symptoms of this pathology.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESA fibromialgia é uma condição dolorosa associada à diversas comorbidades. Embora o mecanismo subjacente à fibromialgia permaneça desconhecido, a depleção de monoaminas, aumento da síntese de espécies reativas de oxigênio (ROS) e disfunção mitocondrial parecem relevantes na sua patogênese. Uma vez que o Receptor de Potencial Transitório Anquirina 1 (TRPA1), um sensor de estresse oxidativo, está envolvido em condições relacionadas à patogênese da fibromialgia, incluindo dor espontânea, dor musculoesquelética, fadiga e comportamentos depressivos e ansiosos, hipotetizamos que o TRPA1 poderia estar envolvido com os sintomas da fibromialgia. O modelo de fibromialgia foi induzido por injeções subcutâneas de reserpina (1 mg/kg), uma vez ao dia por 3 dias consecutivos em camundongos Swiss e C57BL/6J e também em camundongos deficientes de TRPA1. Todos os testes comportamentais foram realizados no 4º dia após a primeira administração de reserpina. Em seguida, os animais foram eutanasiados e diferentes tecidos (músculos gastrocnêmio e sóleo, tecido plantar, nervo ciático e medula espinhal) foram coletados para investigações bioquímicas. A coenzima Q10 e a oligomicina foram usadas para avaliar a função mitocondrial e sintomas característicos da fibromialgia. O ácido α-lipoico foi usado para elucidar o papel do estresse oxidativo no modelo de fibromialgia. O antagonista do canal TRPA1, A-967079, foi utilizado para avaliar o envolvimento do TRPA1, enquanto que a pregabalina ou a duloxetina foram utilizadas como drogas de referência para aliviar os sintomas da fibromialgia. A reserpina reduziu os níveis de monoaminas, causou alodinia mecânica e ao frio, hipersensibilidade química, reduziu a força muscular e o comportamento de escavar, causou comportamento tigmotáxico e aumentou o tempo de imobilidade dos animais no nado forçado. A oligomicina exacerbou os sintomas tipo-fibromialgia induzidos por reserpina, enquanto a coenzima Q10, ácido α-lipoico, A-967079, pregabalina e duloxetina atenuaram diferentes parâmetros nociceptivos e comórbidos induzidos por reserpina. A administração local de reserpina induziu hipersensibilidade aguda. A reserpina induziu disfunção mitocondrial (respirometria de alta resolução) e alterou o estado oxidativo (níveis de ROS e peroxidação lipídica) nos músculos sóleo e gastrocnêmio e na medula espinhal. A reserpina aumentou os níveis de H2O2 no tecido plantar e aumentou a marcação para 4-hidroxinoneal no nervo ciático. Estes parâmetros oxidativos e os sintomas dolorosos tipo-fibromialgia não foram observados quando a reserpina foi administrada em animais deficientes de TRPA1. Deste modo, a disfunção mitocondrial e o estresse oxidativo são mecanismos importantes para a ativação do TRPA1 e, portanto, para o desenvolvimento e manutenção da hipersensibilidade e algumas comorbidades observadas neste modelo de fibromialgia. Desta forma, contribuímos para os avanços nos mecanismos envolvidos com a fisiopatologia da fibromialgia e incitamos a utilização de possíveis novos tratamentos para o controle dos sintomas desta patologia.Universidade Federal de Santa MariaBrasilBioquímicaUFSMPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaCentro de Ciências Naturais e ExatasOliveira, Sara Marchesan dehttp://lattes.cnpq.br/6574555059806902Silva, Cássia Regina daFernandes, Elizabeth SoaresBochi, Guilherme VargasFerreira, JulianoBrum, Evelyne da Silva2022-11-29T12:14:20Z2022-11-29T12:14:20Z2022-09-30info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/27134porAttribution-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:UFSM2022-11-29T12:14:20Zoai:repositorio.ufsm.br:1/27134Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2022-11-29T12:14:20Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Participação do receptor de potencial transitório anquirina 1 e disfunção mitocondrial em um modelo de fibromialgia em camundongos Transient receptor potential ankyrin 1 participation and mitochondrial dysfunction in a mice model of fibromyalgia |
title |
Participação do receptor de potencial transitório anquirina 1 e disfunção mitocondrial em um modelo de fibromialgia em camundongos |
spellingShingle |
Participação do receptor de potencial transitório anquirina 1 e disfunção mitocondrial em um modelo de fibromialgia em camundongos Brum, Evelyne da Silva Dor muscular Dor nociplástica Depressão Respirometria de alta resolução Estresse oxidativo TRPA1 Muscle pain Nociplastic pain Depression High-resolution respirometry Oxidative stress CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Participação do receptor de potencial transitório anquirina 1 e disfunção mitocondrial em um modelo de fibromialgia em camundongos |
title_full |
Participação do receptor de potencial transitório anquirina 1 e disfunção mitocondrial em um modelo de fibromialgia em camundongos |
title_fullStr |
Participação do receptor de potencial transitório anquirina 1 e disfunção mitocondrial em um modelo de fibromialgia em camundongos |
title_full_unstemmed |
Participação do receptor de potencial transitório anquirina 1 e disfunção mitocondrial em um modelo de fibromialgia em camundongos |
title_sort |
Participação do receptor de potencial transitório anquirina 1 e disfunção mitocondrial em um modelo de fibromialgia em camundongos |
author |
Brum, Evelyne da Silva |
author_facet |
Brum, Evelyne da Silva |
author_role |
author |
dc.contributor.none.fl_str_mv |
Oliveira, Sara Marchesan de http://lattes.cnpq.br/6574555059806902 Silva, Cássia Regina da Fernandes, Elizabeth Soares Bochi, Guilherme Vargas Ferreira, Juliano |
dc.contributor.author.fl_str_mv |
Brum, Evelyne da Silva |
dc.subject.por.fl_str_mv |
Dor muscular Dor nociplástica Depressão Respirometria de alta resolução Estresse oxidativo TRPA1 Muscle pain Nociplastic pain Depression High-resolution respirometry Oxidative stress CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
topic |
Dor muscular Dor nociplástica Depressão Respirometria de alta resolução Estresse oxidativo TRPA1 Muscle pain Nociplastic pain Depression High-resolution respirometry Oxidative stress CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
Fibromyalgia is a painful condition associated with several comorbidities. Although the mechanism underlying fibromyalgia remains unknown, monoamine depletion, reactive oxygen species (ROS) overproduction, and mitochondrial dysfunction appear relevant in its pathogenesis. Once Transient Receptor Potential Ankyrin 1 (TRPA1), an oxidative stress sensor, is involved in conditions related to the pathogenesis of fibromyalgia, including spontaneous and musculoskeletal pain, fatigue and depressive and anxiety behaviours, we hypothesized that TRPA1 could be involved with fibromyalgia symptoms. The fibromyalgia model was induced by subcutaneous injections of reserpine (1 mg/kg) once daily for three consecutive days in Swiss and C57BL/6J mice and in TRPA1-deficient mice. All behavioural tests were performed on the 4 th day after the first administration of reserpine. Immediately after, the animals were euthanized, and different tissues (gastrocnemius and soleus muscles, plantar tissue, sciatic nerve, and spinal cord) were collected for biochemical investigations. Coenzyme Q10 and oligomycin were used to assess mitochondrial function and characteristic symptoms of fibromyalgia. α-lipoic acid was used to elucidate the role of oxidative stress in the fibromyalgia model. The TRPA1 antagonist, A-967079, was used to assess TRPA1 involvement, while the pregabalin or duloxetine were used as reference drugs for fibromyalgia symptoms. Reserpine reduced monoamine levels, caused mechanical and cold allodynia, chemical hypersensitivity, reduced muscle strength and burrowing behaviour, caused thigmotaxic behaviour and increased the immobility time of animals in the forced swim test. Oligomycin exacerbated reserpine-induced fibromyalgia-like symptoms, while coenzyme Q10, α-lipoic acid, A-967079, pregabalin, and duloxetine attenuated different reserpine-induced nociceptive and comorbid parameters. Local administration of reserpine induced acute hypersensitivity. Reserpine induced mitochondrial dysfunction (high-resolution respirometry) and altered oxidative status (ROS levels and lipid peroxidation) in the soleus and gastrocnemius muscles and spinal cord. Reserpine increased H2O2 levels in the plantar tissue and increased staining for 4-hydroxynononeal in the sciatic nerve. These oxidative parameters and fibromyalgia-like painful symptoms were not observed when reserpine was administered in TRPA1-deficient mice. Thus, mitochondrial dysfunction and oxidative stress are essential mechanisms for TRPA1 activation and, therefore, for the development and maintenance of the hypersensitivity and some comorbidities observed in this fibromyalgia model. In this way, we contribute to advances in the mechanisms involved in the pathophysiology of fibromyalgia and encourage the use of possible new treatments to control the symptoms of this pathology. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-11-29T12:14:20Z 2022-11-29T12:14:20Z 2022-09-30 |
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/1/27134 |
url |
http://repositorio.ufsm.br/handle/1/27134 |
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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1805922116378296320 |