Fenótipos relacionados à dor em peixe-zebra: uma caracterização neurocomportamental utilizando o modelo de dor visceral induzida pelo ácido acético
Autor(a) principal: | |
---|---|
Data de Publicação: | 2021 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/23582 |
Resumo: | The zebrafish (Danio rerio) is a small freshwater teleost belonging to the Cyprinidae family, which has been studied in different scientific areas. This species has evolutionarily conserved genes and a relatively complex behavioral repertoire, which can be modulated by several pharmacological drugs, such as algogens and analgesic drugs. Although recent studies have shown that zebrafish is an emerging model organism for assessing nociception, specific phenotypes that may indicate local pain are still poorly understood. This thesis aimed to characterize specific behavioral phenotypes in the presence of algogens to validate a model of visceral pain induced by intraperitoneal administration of acetic acid. In a first study, we demonstrated that intraperitoneal injection of acetic acid (2.5 and 5.0%) induced a response similar to the abdominal constriction in rodents, which was assessed by measuring the abdominal curvature index. All doses tested (0.5–5.0%) reduced the distance traveled and vertical activity in the novel tank test. The duration of freezing increased after 5.0% acetic acid, while fish injected with 1.0, 2.5 and 5.0% spent more time in the top area of the tank. Both morphine (an opioid analgesic) and diclofenac (a nonsteroidal anti-inflammatory drug, NSAID) prevented acetic acid-induced changes (5.0%) in the body curvature index, while naloxone antagonized the analgesic effects of morphine. Although morphine attenuates pain-like responses in zebrafish, there are no data showing whether the opioid receptor antagonism prolongs pain duration in the absence of an exogenous opioid. In a second report, we investigated whether a common opioid antagonist, naloxone, affects the constriction-like response. Animals were injected intraperitoneally with acetic acid (5.0%), naloxone (1.25 mg / kg; 2.5 mg / kg; 5.0 mg / kg) or acetic acid with naloxone to investigate changes in the body curvature for 1 h. As expected, acetic acid elicited pain responses in zebrafish for 30 min, while no effect was observed after PBS injection. Although naloxone alone does not change the frequency and duration of this behavior, it dose-dependently prolongs the acetic acid-induced abdominal curvature response, suggesting that endogenous opioids may have a key role in recovering this specific phenotype in the acute visceral pain model. Finally, in the third study, we performed a systematic review on the importance of zebrafish models for pain-related studies. Albeit the anatomical differences between teleost fishes and mammals, orthologs of genes involved in nociception (e.g., opioid receptors, transient potential receptors, acid-sensitive ion channels, and cannabinoid receptors) show a high degree of genetic similarity. These data support the involvement of an evolutionarily conserved cellular machinery for nociceptive responses in zebrafish. Overall, the results obtained here a support a new strategy to assess pain-related behavioral parameters in zebrafish with high predictive, face, and construct validity. |
id |
UFSM_a51af169975080f7d173662035e8c9b3 |
---|---|
oai_identifier_str |
oai:repositorio.ufsm.br:1/23582 |
network_acronym_str |
UFSM |
network_name_str |
Manancial - Repositório Digital da UFSM |
repository_id_str |
|
spelling |
Fenótipos relacionados à dor em peixe-zebra: uma caracterização neurocomportamental utilizando o modelo de dor visceral induzida pelo ácido acéticoPain-like behaviors-related phenotypes in zebrafish: a neurobehavioral characterization using the acetic acid modelPeixe-zebraNocicepçãoDorÁcido acéticoCurvatura abdominalZebrafishNociceptionPainAcetic acidAbdominal curvatureCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAThe zebrafish (Danio rerio) is a small freshwater teleost belonging to the Cyprinidae family, which has been studied in different scientific areas. This species has evolutionarily conserved genes and a relatively complex behavioral repertoire, which can be modulated by several pharmacological drugs, such as algogens and analgesic drugs. Although recent studies have shown that zebrafish is an emerging model organism for assessing nociception, specific phenotypes that may indicate local pain are still poorly understood. This thesis aimed to characterize specific behavioral phenotypes in the presence of algogens to validate a model of visceral pain induced by intraperitoneal administration of acetic acid. In a first study, we demonstrated that intraperitoneal injection of acetic acid (2.5 and 5.0%) induced a response similar to the abdominal constriction in rodents, which was assessed by measuring the abdominal curvature index. All doses tested (0.5–5.0%) reduced the distance traveled and vertical activity in the novel tank test. The duration of freezing increased after 5.0% acetic acid, while fish injected with 1.0, 2.5 and 5.0% spent more time in the top area of the tank. Both morphine (an opioid analgesic) and diclofenac (a nonsteroidal anti-inflammatory drug, NSAID) prevented acetic acid-induced changes (5.0%) in the body curvature index, while naloxone antagonized the analgesic effects of morphine. Although morphine attenuates pain-like responses in zebrafish, there are no data showing whether the opioid receptor antagonism prolongs pain duration in the absence of an exogenous opioid. In a second report, we investigated whether a common opioid antagonist, naloxone, affects the constriction-like response. Animals were injected intraperitoneally with acetic acid (5.0%), naloxone (1.25 mg / kg; 2.5 mg / kg; 5.0 mg / kg) or acetic acid with naloxone to investigate changes in the body curvature for 1 h. As expected, acetic acid elicited pain responses in zebrafish for 30 min, while no effect was observed after PBS injection. Although naloxone alone does not change the frequency and duration of this behavior, it dose-dependently prolongs the acetic acid-induced abdominal curvature response, suggesting that endogenous opioids may have a key role in recovering this specific phenotype in the acute visceral pain model. Finally, in the third study, we performed a systematic review on the importance of zebrafish models for pain-related studies. Albeit the anatomical differences between teleost fishes and mammals, orthologs of genes involved in nociception (e.g., opioid receptors, transient potential receptors, acid-sensitive ion channels, and cannabinoid receptors) show a high degree of genetic similarity. These data support the involvement of an evolutionarily conserved cellular machinery for nociceptive responses in zebrafish. Overall, the results obtained here a support a new strategy to assess pain-related behavioral parameters in zebrafish with high predictive, face, and construct validity.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESO peixe-zebra (Danio rerio) é um pequeno teleósteo de água doce pertencente à família Cyprinidae, o qual vem sendo estudado em diferentes áreas científicas. Essa espécie apresenta genes evolutivamente conservados e um amplo repertório comportamental, os quais podem ser afetados por diversas modulações farmacológicas, tais como algógenos e substâncias analgésicas. Apesar de estudos recentes demonstraram que o peixe-zebra é um organismo modelo emergente para o estudo de processos relacionados à nocicepção, dados relacionados a fenótipos específicos que podem indicar dor localizada ainda carecem de informação. Portanto, a presente tese tem por objetivo caracterizar fenótipos comportamentais específicos na presença de algógenos com ênfase na validação de um novo modelo de dor visceral induzida pela administração intraperitoneal de ácido acético. No primeiro trabalho nós demonstramos que a injeção intraperitoneal de ácido acético (2,5 e 5,0%) promoveu uma resposta semelhante à contorção abdominal em roedores, que foi avaliada pela medição de um índice de curvatura abdominal. Além disso, todas as doses testadas (0,5–5,0%) reduziram a distância percorrida e a atividade vertical no teste do tanque novo. A duração do congelamento aumentou após 5,0% de ácido acético, enquanto os peixes injetados com 1,0, 2,5 e 5,0% aumentaram o tempo de permanência na área superior do tanque. Tanto a morfina (um analgésico opioide) quanto o diclofenaco (um anti-inflamatório não esteroidal, AINE) preveniram as mudanças induzidas pelo ácido acético (5,0%) no índice de curvatura corporal, enquanto a naloxona bloqueou os efeitos analgésicos da morfina. Embora a morfina atenue as respostas semelhantes à dor no peixe-zebra, não há dados mostrando se o antagonismo dos receptores opioides prolonga a duração da dor na ausência de um opioide exógeno. Portanto, em um segundo trabalho, nós investigamos se um antagonista opioide comum, naloxona, afeta a resposta semelhante a constrição abdominal. Os animais foram injetados intraperitonealmente com ácido acético (5,0%), naloxona (1,25 mg / kg; 2,5 mg / kg; 5,0 mg / kg) ou ácido acético com naloxona para investigar as mudanças na curvatura corporal por 1 h. O ácido acético provocou uma resposta semelhante a dor no peixe-zebra, conforme avaliado pelo índice de curvatura abdominal que dura aproximadamente 30 min, enquanto nenhum efeito foi observado após a injeção de PBS. Embora a naloxona sozinha não altere a frequência e a duração desse comportamento, ela prolonga de forma dependente de dose a resposta da curvatura abdominal induzida pelo ácido acético, sugerindo que opioides endógenos podem ter um papel chave na recuperação deste fenótipo específico no modelo de dor visceral aguda. Por fim, no terceiro trabalho, nós realizamos uma revisão sistemática sobre a importância dos modelos utilizando peixe-zebra para estudos relacionados à dor. Mesmo com estruturas anatômicas distintas às dos mamíferos, ortólogos de genes envolvidos na nocicepção (ex: receptores opioides, receptores de potencial transitório, canais iônicos sensíveis ao ácido e receptores canabinoides) apresentam alto grau de similaridade genética. Em suma, esses dados corroboram o envolvimento de uma maquinaria celular evolutivamente conservada para respostas nociceptivas em peixe-zebra. De modo geral, os resultados obtidos nesta tese suportam uma nova estratégia para avaliar parâmetros comportamentais relacionados à dor no peixe-zebra com alto valor preditivo, de face e construto.Universidade Federal de Santa MariaBrasilBioquímicaUFSMPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaCentro de Ciências Naturais e ExatasRosemberg, Denis Broockhttp://lattes.cnpq.br/7713953979203056Barreto, Rodrigo EgydioBonan, Carla DeniseRubin, Maribel AntonelloSilva, Anderson Manoel Herculano Oliveira daCosta, Fabiano de Vargas da2022-01-19T13:39:08Z2022-01-19T13:39:08Z2021-08-26info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/23582porAttribution-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:UFSM2022-01-19T13:41:02Zoai:repositorio.ufsm.br:1/23582Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2022-01-19T13:41:02Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Fenótipos relacionados à dor em peixe-zebra: uma caracterização neurocomportamental utilizando o modelo de dor visceral induzida pelo ácido acético Pain-like behaviors-related phenotypes in zebrafish: a neurobehavioral characterization using the acetic acid model |
title |
Fenótipos relacionados à dor em peixe-zebra: uma caracterização neurocomportamental utilizando o modelo de dor visceral induzida pelo ácido acético |
spellingShingle |
Fenótipos relacionados à dor em peixe-zebra: uma caracterização neurocomportamental utilizando o modelo de dor visceral induzida pelo ácido acético Costa, Fabiano de Vargas da Peixe-zebra Nocicepção Dor Ácido acético Curvatura abdominal Zebrafish Nociception Pain Acetic acid Abdominal curvature CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Fenótipos relacionados à dor em peixe-zebra: uma caracterização neurocomportamental utilizando o modelo de dor visceral induzida pelo ácido acético |
title_full |
Fenótipos relacionados à dor em peixe-zebra: uma caracterização neurocomportamental utilizando o modelo de dor visceral induzida pelo ácido acético |
title_fullStr |
Fenótipos relacionados à dor em peixe-zebra: uma caracterização neurocomportamental utilizando o modelo de dor visceral induzida pelo ácido acético |
title_full_unstemmed |
Fenótipos relacionados à dor em peixe-zebra: uma caracterização neurocomportamental utilizando o modelo de dor visceral induzida pelo ácido acético |
title_sort |
Fenótipos relacionados à dor em peixe-zebra: uma caracterização neurocomportamental utilizando o modelo de dor visceral induzida pelo ácido acético |
author |
Costa, Fabiano de Vargas da |
author_facet |
Costa, Fabiano de Vargas da |
author_role |
author |
dc.contributor.none.fl_str_mv |
Rosemberg, Denis Broock http://lattes.cnpq.br/7713953979203056 Barreto, Rodrigo Egydio Bonan, Carla Denise Rubin, Maribel Antonello Silva, Anderson Manoel Herculano Oliveira da |
dc.contributor.author.fl_str_mv |
Costa, Fabiano de Vargas da |
dc.subject.por.fl_str_mv |
Peixe-zebra Nocicepção Dor Ácido acético Curvatura abdominal Zebrafish Nociception Pain Acetic acid Abdominal curvature CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
topic |
Peixe-zebra Nocicepção Dor Ácido acético Curvatura abdominal Zebrafish Nociception Pain Acetic acid Abdominal curvature CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
The zebrafish (Danio rerio) is a small freshwater teleost belonging to the Cyprinidae family, which has been studied in different scientific areas. This species has evolutionarily conserved genes and a relatively complex behavioral repertoire, which can be modulated by several pharmacological drugs, such as algogens and analgesic drugs. Although recent studies have shown that zebrafish is an emerging model organism for assessing nociception, specific phenotypes that may indicate local pain are still poorly understood. This thesis aimed to characterize specific behavioral phenotypes in the presence of algogens to validate a model of visceral pain induced by intraperitoneal administration of acetic acid. In a first study, we demonstrated that intraperitoneal injection of acetic acid (2.5 and 5.0%) induced a response similar to the abdominal constriction in rodents, which was assessed by measuring the abdominal curvature index. All doses tested (0.5–5.0%) reduced the distance traveled and vertical activity in the novel tank test. The duration of freezing increased after 5.0% acetic acid, while fish injected with 1.0, 2.5 and 5.0% spent more time in the top area of the tank. Both morphine (an opioid analgesic) and diclofenac (a nonsteroidal anti-inflammatory drug, NSAID) prevented acetic acid-induced changes (5.0%) in the body curvature index, while naloxone antagonized the analgesic effects of morphine. Although morphine attenuates pain-like responses in zebrafish, there are no data showing whether the opioid receptor antagonism prolongs pain duration in the absence of an exogenous opioid. In a second report, we investigated whether a common opioid antagonist, naloxone, affects the constriction-like response. Animals were injected intraperitoneally with acetic acid (5.0%), naloxone (1.25 mg / kg; 2.5 mg / kg; 5.0 mg / kg) or acetic acid with naloxone to investigate changes in the body curvature for 1 h. As expected, acetic acid elicited pain responses in zebrafish for 30 min, while no effect was observed after PBS injection. Although naloxone alone does not change the frequency and duration of this behavior, it dose-dependently prolongs the acetic acid-induced abdominal curvature response, suggesting that endogenous opioids may have a key role in recovering this specific phenotype in the acute visceral pain model. Finally, in the third study, we performed a systematic review on the importance of zebrafish models for pain-related studies. Albeit the anatomical differences between teleost fishes and mammals, orthologs of genes involved in nociception (e.g., opioid receptors, transient potential receptors, acid-sensitive ion channels, and cannabinoid receptors) show a high degree of genetic similarity. These data support the involvement of an evolutionarily conserved cellular machinery for nociceptive responses in zebrafish. Overall, the results obtained here a support a new strategy to assess pain-related behavioral parameters in zebrafish with high predictive, face, and construct validity. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-08-26 2022-01-19T13:39:08Z 2022-01-19T13:39:08Z |
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/1/23582 |
url |
http://repositorio.ufsm.br/handle/1/23582 |
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 |
_version_ |
1805922136815042560 |