Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP
Autor(a) principal: | |
---|---|
Data de Publicação: | 2018 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFU |
Texto Completo: | https://repositorio.ufu.br/handle/123456789/22723 http://dx.doi.org/10.14393/ufu.te.2018.489 |
Resumo: | Introduction: Diabetes is a group of metabolic diseases characterized by hyperglycemia, which is growing and relevant problem for public health. Chronic hyperglycemia eventually results in the development of diabetic neuropathy, which often causes chronic pain, difficult to treat. The mechanisms responsible for the development of painful diabetic neuropathy are not well known, but some studies suggest that alterations in ion channels expressed by nociceptive neurons might be involved. Objectives: To study the direct effect of hyperglycemia on the resting membrane potential of primary nociceptive neurons and the nociceptive mechanical threshold in rats. To investigate the involvement of potassium channels sensitive to ATP (K+ATP) in this process. Material and methods: Variations in membrane potential were recorded by confocal microscopy using the fluorescence variation emitted by primary cultured neurons of the dorsal root ganglia in the presence of the fluorescent indicator DiBAC4(3). It was tested the effect of different glucose concentrations, insulin, the K+ATP channel blocker glibenclamide, and the K+ATP channel activator diazoxide. The mechanical sensitivity threshold of rats treated in vivo with intraganglionar injection (L5) of different concentrations of glucose, mannitol and diazoxide was evaluated using the electronic von Frey test. Results: High glucose concentrations (300, 450 and 600 mg/dL) induced depolarization of dorsal root ganglion neurons in culture in a concentrationdependent manner. Changes in resting membrane potential were not due to the addition of a hyperosmotic solution, which was tested by the administration of an isosmotic glucose solution (600 mg/dL). In vitro, insulin administration (1 μM) inhibited glucose-induced depolarization as well as diazoxide (10 μM), a K+ATP channel openner. Glibenclamide (10 μM), a K+ATP channel blocker, caused depolarization of cultured neurons. Intraganglionar injection (L5) of high concentrations of glucose, in vivo, induced a state of hyperalgesia detected by a reduced mechanical threshold. Co-administration of diazoxide (10 μM) inhibited glucose induced hyperalgesia. Injection of hyperosmotic solution of mannitol, which is metabolically inert, did not cause changes in the mechanical threshold, indicating that changes in osmolarity are not responsible for the effect of glucose in vivo. Conclusion: Results suggest that closure K+ATP channels expressed in peripheral sensory neurons are responsible for a direct glucose effect on nociceptive neurons and, therefore, might be involved in the development of diabetic painful neuropathy. Since sulfonylureas (like glibenclamide, for example) that act by blocking K+ATP are used to treat type 2 diabeticpatients, it is important to evaluate possible side effects of such drugs at primary sensory neurons. |
id |
UFU_b7ac365c31c3598556583f44849dd545 |
---|---|
oai_identifier_str |
oai:repositorio.ufu.br:123456789/22723 |
network_acronym_str |
UFU |
network_name_str |
Repositório Institucional da UFU |
repository_id_str |
|
spelling |
Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATPHyperglycemia induces mechanical hyperalgesia and depolarization of the resting membrane potential of primary nociceptive neurons: role of ATP-sensitive potassium channelsCanais K+ATPDiabetesGânglio da raiz dorsalHiperglicemiaNeuropatiaNocicepçãoDorsal root gangliaHyperglycemiaK+ATP channelsNeuropathyNociceptionCiências médicasNeuropatias diabéticasCNPQ::CIENCIAS BIOLOGICAS::FISIOLOGIA::FISIOLOGIA GERAL::NEUROFISIOLOGIAIntroduction: Diabetes is a group of metabolic diseases characterized by hyperglycemia, which is growing and relevant problem for public health. Chronic hyperglycemia eventually results in the development of diabetic neuropathy, which often causes chronic pain, difficult to treat. The mechanisms responsible for the development of painful diabetic neuropathy are not well known, but some studies suggest that alterations in ion channels expressed by nociceptive neurons might be involved. Objectives: To study the direct effect of hyperglycemia on the resting membrane potential of primary nociceptive neurons and the nociceptive mechanical threshold in rats. To investigate the involvement of potassium channels sensitive to ATP (K+ATP) in this process. Material and methods: Variations in membrane potential were recorded by confocal microscopy using the fluorescence variation emitted by primary cultured neurons of the dorsal root ganglia in the presence of the fluorescent indicator DiBAC4(3). It was tested the effect of different glucose concentrations, insulin, the K+ATP channel blocker glibenclamide, and the K+ATP channel activator diazoxide. The mechanical sensitivity threshold of rats treated in vivo with intraganglionar injection (L5) of different concentrations of glucose, mannitol and diazoxide was evaluated using the electronic von Frey test. Results: High glucose concentrations (300, 450 and 600 mg/dL) induced depolarization of dorsal root ganglion neurons in culture in a concentrationdependent manner. Changes in resting membrane potential were not due to the addition of a hyperosmotic solution, which was tested by the administration of an isosmotic glucose solution (600 mg/dL). In vitro, insulin administration (1 μM) inhibited glucose-induced depolarization as well as diazoxide (10 μM), a K+ATP channel openner. Glibenclamide (10 μM), a K+ATP channel blocker, caused depolarization of cultured neurons. Intraganglionar injection (L5) of high concentrations of glucose, in vivo, induced a state of hyperalgesia detected by a reduced mechanical threshold. Co-administration of diazoxide (10 μM) inhibited glucose induced hyperalgesia. Injection of hyperosmotic solution of mannitol, which is metabolically inert, did not cause changes in the mechanical threshold, indicating that changes in osmolarity are not responsible for the effect of glucose in vivo. Conclusion: Results suggest that closure K+ATP channels expressed in peripheral sensory neurons are responsible for a direct glucose effect on nociceptive neurons and, therefore, might be involved in the development of diabetic painful neuropathy. Since sulfonylureas (like glibenclamide, for example) that act by blocking K+ATP are used to treat type 2 diabeticpatients, it is important to evaluate possible side effects of such drugs at primary sensory neurons.Tese (Doutorado)Introdução: A diabetes é um grupo de doenças metabólicas caracterizado por hiperglicemia e é um problema crescente e relevante de saúde pública. A hiperglicemia crônica resulta no desenvolvimento de neuropatia diabética, que muitas vezes ocasiona dor crônica difícil de ser tratada. Os mecanismos responsáveis pelo desenvolvimento de neuropatia diabética dolorosa não são bem conhecidos, mas alguns estudos sugerem que alterações nos canais iônicos de neurônios nociceptivos parecem estar envolvidas. Objetivos: Estudar o efeito direto da hiperglicemia sobre o potencial de repouso de neurônios nociceptivos primários e sobre o limiar mecânico nociceptivo, além de investigar o envolvimento dos canais de potássio sensíveis ao ATP (K+ATP) nesses processos. Material e Métodos: Foram realizadas culturas primárias de neurônios dos gânglios da raiz dorsal (GRD) de ratos adultos e as variações no potencial de membrana foram registradas por microscopia confocal através da variação de fluorescência emitida pelos neurônios na presença do indicador DiBAC4(3). Avaliou-se o efeito da administração de glicose em diferentes concentrações, insulina, um bloqueador de canais K+ATP, a glibenclamida, e um ativador de canais K+ATP, o diazóxido nos neurônios em cultura. Também foi avaliado o limiar de sensibilidade mecânica de animais tratados in vivo com injeção intraganglionar (L5) de diferentes concentrações de glicose, manitol e diazóxido, utilizando o teste von Frey eletrônico. Resultados: Altas concentrações de glicose (300, 450 e 600 mg/dL) causaram despolarização de neurônios do gânglio da raiz dorsal em cultura de maneira dependente de concentração, e essa alteração no potencial de repouso das células não ocorreu devido a adição de uma solução hiperosmótica, o que foi comprovado com a administração de uma solução isosmótica de glicose (600 mg/dL). In vitro, a administração de insulina (1 µM) inibiu a despolarização induzida por glicose, assim como o diazóxido (10 µM), um ativador de canais K+ATP. Glibenclamida (10 µM), um bloqueador de canais K+ATP, provocou despolarização dos neurônios em cultura assim como a glicose. A injeção de altas concentrações de glicose por via intraganglionar (L5), in vivo, induziu um estado de hiperalgesia nos animais. A injeção do ativador diazóxido (10 µM) aumentou o limiar de sensibilidade mecânica que havia diminuido com a injeção de glicose. A injeção de solução hiperosmótica de manitol, que é inerte metabolicamente, não provocou alterações no limiar mecânico, indicando que alterações na osmolaridade não são responsáveis pelo efeito da glicose in vivo. Conclusão: Em conclusão, esse estudo sugere que os canais K+ATP expressos nos neurônios sensoriais periféricos podem estar envolvidos no desenvolvimento da neuropatia diabética periférica. Como as sulfonilureias (como a glibenclamida, por exemplo),que agem bloqueando a abertura de canais K+ATP são usadas no tratamento de pacientes com diabetes tipo 2, é muito importante avaliar os possíveis efeitos colaterais de tais drogas nos neurônios sensoriais primários.Universidade Federal de UberlândiaBrasilPrograma de Pós-graduação em Ciências da SaúdeLotufo, Celina Monteiro da Cruzhttp://lattes.cnpq.br/5829636849353650Duarte, Djane Brazhttp://lattes.cnpq.br/5218764042751604Rodrigues, Aldo Rogelis Aquileshttp://lattes.cnpq.br/6645292290768657Silva, Cassia Regina dahttp://lattes.cnpq.br/3670843400502958Zanon, Renata Gracielehttp://lattes.cnpq.br/2943313641276308Lima, Taís de Campos2018-10-26T21:25:27Z2018-10-26T21:25:27Z2018-08-27info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfLIMA, Taís de Campos. Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP. 2018. 69 f. Tese (Doutorado em Ciências da Saúde) - Universidade Federal de Uberlândia, Uberlândia, 2018. DOI http://dx.doi.org/10.14393/ufu.te.2018.489https://repositorio.ufu.br/handle/123456789/22723http://dx.doi.org/10.14393/ufu.te.2018.489porinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFUinstname:Universidade Federal de Uberlândia (UFU)instacron:UFU2018-10-26T21:25:28Zoai:repositorio.ufu.br:123456789/22723Repositório InstitucionalONGhttp://repositorio.ufu.br/oai/requestdiinf@dirbi.ufu.bropendoar:2018-10-26T21:25:28Repositório Institucional da UFU - Universidade Federal de Uberlândia (UFU)false |
dc.title.none.fl_str_mv |
Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP Hyperglycemia induces mechanical hyperalgesia and depolarization of the resting membrane potential of primary nociceptive neurons: role of ATP-sensitive potassium channels |
title |
Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP |
spellingShingle |
Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP Lima, Taís de Campos Canais K+ATP Diabetes Gânglio da raiz dorsal Hiperglicemia Neuropatia Nocicepção Dorsal root ganglia Hyperglycemia K+ATP channels Neuropathy Nociception Ciências médicas Neuropatias diabéticas CNPQ::CIENCIAS BIOLOGICAS::FISIOLOGIA::FISIOLOGIA GERAL::NEUROFISIOLOGIA |
title_short |
Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP |
title_full |
Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP |
title_fullStr |
Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP |
title_full_unstemmed |
Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP |
title_sort |
Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP |
author |
Lima, Taís de Campos |
author_facet |
Lima, Taís de Campos |
author_role |
author |
dc.contributor.none.fl_str_mv |
Lotufo, Celina Monteiro da Cruz http://lattes.cnpq.br/5829636849353650 Duarte, Djane Braz http://lattes.cnpq.br/5218764042751604 Rodrigues, Aldo Rogelis Aquiles http://lattes.cnpq.br/6645292290768657 Silva, Cassia Regina da http://lattes.cnpq.br/3670843400502958 Zanon, Renata Graciele http://lattes.cnpq.br/2943313641276308 |
dc.contributor.author.fl_str_mv |
Lima, Taís de Campos |
dc.subject.por.fl_str_mv |
Canais K+ATP Diabetes Gânglio da raiz dorsal Hiperglicemia Neuropatia Nocicepção Dorsal root ganglia Hyperglycemia K+ATP channels Neuropathy Nociception Ciências médicas Neuropatias diabéticas CNPQ::CIENCIAS BIOLOGICAS::FISIOLOGIA::FISIOLOGIA GERAL::NEUROFISIOLOGIA |
topic |
Canais K+ATP Diabetes Gânglio da raiz dorsal Hiperglicemia Neuropatia Nocicepção Dorsal root ganglia Hyperglycemia K+ATP channels Neuropathy Nociception Ciências médicas Neuropatias diabéticas CNPQ::CIENCIAS BIOLOGICAS::FISIOLOGIA::FISIOLOGIA GERAL::NEUROFISIOLOGIA |
description |
Introduction: Diabetes is a group of metabolic diseases characterized by hyperglycemia, which is growing and relevant problem for public health. Chronic hyperglycemia eventually results in the development of diabetic neuropathy, which often causes chronic pain, difficult to treat. The mechanisms responsible for the development of painful diabetic neuropathy are not well known, but some studies suggest that alterations in ion channels expressed by nociceptive neurons might be involved. Objectives: To study the direct effect of hyperglycemia on the resting membrane potential of primary nociceptive neurons and the nociceptive mechanical threshold in rats. To investigate the involvement of potassium channels sensitive to ATP (K+ATP) in this process. Material and methods: Variations in membrane potential were recorded by confocal microscopy using the fluorescence variation emitted by primary cultured neurons of the dorsal root ganglia in the presence of the fluorescent indicator DiBAC4(3). It was tested the effect of different glucose concentrations, insulin, the K+ATP channel blocker glibenclamide, and the K+ATP channel activator diazoxide. The mechanical sensitivity threshold of rats treated in vivo with intraganglionar injection (L5) of different concentrations of glucose, mannitol and diazoxide was evaluated using the electronic von Frey test. Results: High glucose concentrations (300, 450 and 600 mg/dL) induced depolarization of dorsal root ganglion neurons in culture in a concentrationdependent manner. Changes in resting membrane potential were not due to the addition of a hyperosmotic solution, which was tested by the administration of an isosmotic glucose solution (600 mg/dL). In vitro, insulin administration (1 μM) inhibited glucose-induced depolarization as well as diazoxide (10 μM), a K+ATP channel openner. Glibenclamide (10 μM), a K+ATP channel blocker, caused depolarization of cultured neurons. Intraganglionar injection (L5) of high concentrations of glucose, in vivo, induced a state of hyperalgesia detected by a reduced mechanical threshold. Co-administration of diazoxide (10 μM) inhibited glucose induced hyperalgesia. Injection of hyperosmotic solution of mannitol, which is metabolically inert, did not cause changes in the mechanical threshold, indicating that changes in osmolarity are not responsible for the effect of glucose in vivo. Conclusion: Results suggest that closure K+ATP channels expressed in peripheral sensory neurons are responsible for a direct glucose effect on nociceptive neurons and, therefore, might be involved in the development of diabetic painful neuropathy. Since sulfonylureas (like glibenclamide, for example) that act by blocking K+ATP are used to treat type 2 diabeticpatients, it is important to evaluate possible side effects of such drugs at primary sensory neurons. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-10-26T21:25:27Z 2018-10-26T21:25:27Z 2018-08-27 |
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 |
LIMA, Taís de Campos. Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP. 2018. 69 f. Tese (Doutorado em Ciências da Saúde) - Universidade Federal de Uberlândia, Uberlândia, 2018. DOI http://dx.doi.org/10.14393/ufu.te.2018.489 https://repositorio.ufu.br/handle/123456789/22723 http://dx.doi.org/10.14393/ufu.te.2018.489 |
identifier_str_mv |
LIMA, Taís de Campos. Hiperglicemia induz hiperalgesia mecânica e despolarização do potencial de repouso da membrana de neurônios nociceptivos primários: papel dos canais de potássio sensíveis ao ATP. 2018. 69 f. Tese (Doutorado em Ciências da Saúde) - Universidade Federal de Uberlândia, Uberlândia, 2018. DOI http://dx.doi.org/10.14393/ufu.te.2018.489 |
url |
https://repositorio.ufu.br/handle/123456789/22723 http://dx.doi.org/10.14393/ufu.te.2018.489 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Uberlândia Brasil Programa de Pós-graduação em Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Uberlândia Brasil Programa de Pós-graduação em Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFU instname:Universidade Federal de Uberlândia (UFU) instacron:UFU |
instname_str |
Universidade Federal de Uberlândia (UFU) |
instacron_str |
UFU |
institution |
UFU |
reponame_str |
Repositório Institucional da UFU |
collection |
Repositório Institucional da UFU |
repository.name.fl_str_mv |
Repositório Institucional da UFU - Universidade Federal de Uberlândia (UFU) |
repository.mail.fl_str_mv |
diinf@dirbi.ufu.br |
_version_ |
1813711533996244992 |