FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and Palmitoylethanolamide
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | por |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://doi.org/10.24915/aup.34.3-4.14 |
Resumo: | Introduction: We aim to study the effect of fatty acid amide hydrolase (FAAH) blockade on bladder hyperactivity and on fatty acid amides levels during cystitis. Material and Methods: Cystitis was induced in female Wistar rats using 5 mg/mL lipopolysaccharide (LPS). Control group were intravesical instilled with saline. LPS and control groups received intravenously (caudal vein) during cystometry: URB 937 (URB; FAAH antagonist) in doses of 0.007, 0.07, 0.7 and 7 mg/kg (cumulative, with 10 minutes interval). Using the maximal effective dose of URB (0.7 mg/kg, see below) animals received 10 uM MJ15 (CB1 receptor antagonist) or 0.3 mg SR144528 /kg (SR; CB2 receptor antagonist). At dose of 7 mg/kg, animals receive 1.4 μg SB366791/kg (SB; TRPV1 antagonist). Control and inflamed (without and with 0.7 and 7 mg/kg URB) group were euthanized and the bladder was harvested for the determination of anandamide (AEA) and palmitoylethanolamide (PEA) by mass spectrometry. Results: Frequency of control was not changed by URB treatment at any dose. LPS increase bladder frequency. 0.007 mg and 0.07 mg URB decrease bladder frequency of LPS-inflamed rats. 0.7 URB reversed LPS-induced bladder hyperactivity. At 7 mg, URB was unable to reverse or reduce LPS-induced bladder hyperactivity. The administration of CB1, CB2 and TRPV1 antagonists did not change the frequency of voiding contractions of naïve animals. CB1 antagonist reversed the effect of 0.7 URB while TRPV1 antagonist reduced the effect of 7 URB. AEA levels increase during inflammation. Treating LPS-inflamed animals with 0.7 mg URB brought AEA levels to control levels. Treating LPS-inflamed animals with 7 mg URB did not change AEA levels, compared to LPS-inflamed animals. PEA levels decrease during inflammation. Treating LPS-inflamed animals with 0.7 mg URB brought AEA levels to control levels. Treating LPS-inflamed animals with 7 mg URB, decreased PEA levels to values similar to the ones observed in LPS- -inflamed animals. Conclusion: During cystitis, the FAAH inhibitor raises the levels of PEA and reverses the urinary frequency by a CB1 receptor- mediated mechanism. When used in very high doses, the FAAH antagonist raises the levels of AEA and increases the urinary frequency by a TRPV1-dependent mechanism. Therefore, the choice of FAAH inhibitor dosage to be used in the clinics should consider the putative effects over the endocannabinoid levels in the system. |
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FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and PalmitoylethanolamideOs Inibidores da FAAH Melhoram a Função das Bexigas Inflamadas, Modulando os Níveis de Anandamide e Palmitoil EtanolamidaAnti-Inflammatory AgentsArachidonic AcidsEndocannabinoidsPalmitic AcidsPainUrinary BladderÁcidos AraquidónicosÁcidos PalmíticosAnti-InflamatóriosBexiga UrináriaDorEndocanabinóidesIntroduction: We aim to study the effect of fatty acid amide hydrolase (FAAH) blockade on bladder hyperactivity and on fatty acid amides levels during cystitis. Material and Methods: Cystitis was induced in female Wistar rats using 5 mg/mL lipopolysaccharide (LPS). Control group were intravesical instilled with saline. LPS and control groups received intravenously (caudal vein) during cystometry: URB 937 (URB; FAAH antagonist) in doses of 0.007, 0.07, 0.7 and 7 mg/kg (cumulative, with 10 minutes interval). Using the maximal effective dose of URB (0.7 mg/kg, see below) animals received 10 uM MJ15 (CB1 receptor antagonist) or 0.3 mg SR144528 /kg (SR; CB2 receptor antagonist). At dose of 7 mg/kg, animals receive 1.4 μg SB366791/kg (SB; TRPV1 antagonist). Control and inflamed (without and with 0.7 and 7 mg/kg URB) group were euthanized and the bladder was harvested for the determination of anandamide (AEA) and palmitoylethanolamide (PEA) by mass spectrometry. Results: Frequency of control was not changed by URB treatment at any dose. LPS increase bladder frequency. 0.007 mg and 0.07 mg URB decrease bladder frequency of LPS-inflamed rats. 0.7 URB reversed LPS-induced bladder hyperactivity. At 7 mg, URB was unable to reverse or reduce LPS-induced bladder hyperactivity. The administration of CB1, CB2 and TRPV1 antagonists did not change the frequency of voiding contractions of naïve animals. CB1 antagonist reversed the effect of 0.7 URB while TRPV1 antagonist reduced the effect of 7 URB. AEA levels increase during inflammation. Treating LPS-inflamed animals with 0.7 mg URB brought AEA levels to control levels. Treating LPS-inflamed animals with 7 mg URB did not change AEA levels, compared to LPS-inflamed animals. PEA levels decrease during inflammation. Treating LPS-inflamed animals with 0.7 mg URB brought AEA levels to control levels. Treating LPS-inflamed animals with 7 mg URB, decreased PEA levels to values similar to the ones observed in LPS- -inflamed animals. Conclusion: During cystitis, the FAAH inhibitor raises the levels of PEA and reverses the urinary frequency by a CB1 receptor- mediated mechanism. When used in very high doses, the FAAH antagonist raises the levels of AEA and increases the urinary frequency by a TRPV1-dependent mechanism. Therefore, the choice of FAAH inhibitor dosage to be used in the clinics should consider the putative effects over the endocannabinoid levels in the system.Introdução: O objectivo foi estudar o efeito do bloqueio da hidrolase da amida dos ácidos gordos na bexiga hiperativa e dos níveis de amidas de ácidos gordos durante a cistite. Material e Métodos: A cistite foi induzida em fêmeas de ratazanas Wistar usando lipopolissacarídeo a 5 mg/mL. O grupo controlo foi instilado com solução salina. Ambos os grupos receberam intravenosamente (veia caudal), durante cistometria: URB 937 (URB; antagonista da hidrolase da amida dos ácidos gordos - FAAH) em doses de 0,007, 0,07, 0,7 e 7 mg/kg (cumulativamente, com 10 minutos de intervalo). Usando a dose máxima efetiva de URB (0,7 mg/kg, ver em baixo) os animais receberam intravenosamente 10 uM MJ15 (antagonista do recetor CB1) ou 0,3 mg SR144528 /kg (SR; antagonista do recetor CB2). Em doses de 7 mg/kg, os animais receberam 1,4 μg SB366791/kg (SB; antagonista do TRPV1). Grupos de animais controlo e com cistite (sem receberem ou depois de receberem 0,7 e 7 mg/kg URB) foram eutanasiados e as bexigas foram colhidas para determinação dos níveis de anandamida (AEA) e palmitoil etanolamida (PEA) por espetrometria de massa. Resultados: A frequência dos animais controlo não se alterou com o tratamento de URB. Na cistite, houve um aumento da frequência urinária. URB nas doses de 0,007 mg/kg e 0,07 mg/ kg fez diminuir a frequência urinária dos animais com cistite. Na dose de 0,7 mg/kg, o URB reverteu a hiperatividade vesical induzida pela cistite. Na dose de 7 mg/kg, URB não reverteu nem reduziu a hiperatividade vesical induzida pela cistite. A administração dos antagonistas dos recetores CB1, CB2 e TRPV1 não alterou a frequência urinária dos animais controlo. O antagonista do recetor CB1 reverteu o efeito induzido por 0,7 mg URB/kg enquanto o antagonista do TRPV1 reduziu o efeito induzido por 7 mg URB/kg. Os níveis de AEA na bexiga aumentaram com a cistite. A administração de 0,7 mg URB/kg aos animais com cistite baixou níveis de AEA para níveis semelhantes aos dos animais controlo. A administração de 7 mg URB/kg em animais com cistite não alterou os níveis de AEA, comparando com os animais com cistite. Os níveis de PEA diminuíram com a cistite. A administração de 0,7 mg URB/kg aos animais com cistite elevou os níveis de PEA para valores semelhantes aos dos animais controlo. A administração de 7 mg URB/kg em animais com cistite baixou níveis de PEA para níveis semelhantes aos dos animais com cistite. Conclusão: Na cistite, o inibidor da FAAH aumentou os níveis da PEA e reverteu a frequência urinária, por um mecanismo que envolve o recetor CB1. Quando usado em doses muito elevadas, o antagonista da FAAH aumenta os níveis de AEA e aumenta da frequência urinária por um mecanismo dependente do TRPV1. Assim sendo, a escolha da dose do inibidor da FAAH a ser usado na clínica deverá considerar os efeitos putativos sobre os níveis de endocanabinóide no sistema.Associação Portuguesa de Urologia2017-12-17T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://doi.org/10.24915/aup.34.3-4.14oai:oai.actaurologicaportuguesa.com:article/14Acta Urológica Portuguesa; Vol. 34 No. 3-4 (2017): july-september; october-december; 21-28Acta Urológica Portuguesa; v. 34 n. 3-4 (2017): julho-setembro; outubro-dezembro; 21-282387-04192341-4022reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAPporhttp://www.actaurologicaportuguesa.com/index.php/aup/article/view/14https://doi.org/10.24915/aup.34.3-4.14http://www.actaurologicaportuguesa.com/index.php/aup/article/view/14/24Charrua, AnaMatos, RitaMarczylo, TimNagy, IstvanCruz, Franciscoinfo:eu-repo/semantics/openAccess2022-09-21T09:04:45Zoai:oai.actaurologicaportuguesa.com:article/14Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T15:55:52.132727Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and Palmitoylethanolamide Os Inibidores da FAAH Melhoram a Função das Bexigas Inflamadas, Modulando os Níveis de Anandamide e Palmitoil Etanolamida |
title |
FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and Palmitoylethanolamide |
spellingShingle |
FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and Palmitoylethanolamide Charrua, Ana Anti-Inflammatory Agents Arachidonic Acids Endocannabinoids Palmitic Acids Pain Urinary Bladder Ácidos Araquidónicos Ácidos Palmíticos Anti-Inflamatórios Bexiga Urinária Dor Endocanabinóides |
title_short |
FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and Palmitoylethanolamide |
title_full |
FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and Palmitoylethanolamide |
title_fullStr |
FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and Palmitoylethanolamide |
title_full_unstemmed |
FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and Palmitoylethanolamide |
title_sort |
FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and Palmitoylethanolamide |
author |
Charrua, Ana |
author_facet |
Charrua, Ana Matos, Rita Marczylo, Tim Nagy, Istvan Cruz, Francisco |
author_role |
author |
author2 |
Matos, Rita Marczylo, Tim Nagy, Istvan Cruz, Francisco |
author2_role |
author author author author |
dc.contributor.author.fl_str_mv |
Charrua, Ana Matos, Rita Marczylo, Tim Nagy, Istvan Cruz, Francisco |
dc.subject.por.fl_str_mv |
Anti-Inflammatory Agents Arachidonic Acids Endocannabinoids Palmitic Acids Pain Urinary Bladder Ácidos Araquidónicos Ácidos Palmíticos Anti-Inflamatórios Bexiga Urinária Dor Endocanabinóides |
topic |
Anti-Inflammatory Agents Arachidonic Acids Endocannabinoids Palmitic Acids Pain Urinary Bladder Ácidos Araquidónicos Ácidos Palmíticos Anti-Inflamatórios Bexiga Urinária Dor Endocanabinóides |
description |
Introduction: We aim to study the effect of fatty acid amide hydrolase (FAAH) blockade on bladder hyperactivity and on fatty acid amides levels during cystitis. Material and Methods: Cystitis was induced in female Wistar rats using 5 mg/mL lipopolysaccharide (LPS). Control group were intravesical instilled with saline. LPS and control groups received intravenously (caudal vein) during cystometry: URB 937 (URB; FAAH antagonist) in doses of 0.007, 0.07, 0.7 and 7 mg/kg (cumulative, with 10 minutes interval). Using the maximal effective dose of URB (0.7 mg/kg, see below) animals received 10 uM MJ15 (CB1 receptor antagonist) or 0.3 mg SR144528 /kg (SR; CB2 receptor antagonist). At dose of 7 mg/kg, animals receive 1.4 μg SB366791/kg (SB; TRPV1 antagonist). Control and inflamed (without and with 0.7 and 7 mg/kg URB) group were euthanized and the bladder was harvested for the determination of anandamide (AEA) and palmitoylethanolamide (PEA) by mass spectrometry. Results: Frequency of control was not changed by URB treatment at any dose. LPS increase bladder frequency. 0.007 mg and 0.07 mg URB decrease bladder frequency of LPS-inflamed rats. 0.7 URB reversed LPS-induced bladder hyperactivity. At 7 mg, URB was unable to reverse or reduce LPS-induced bladder hyperactivity. The administration of CB1, CB2 and TRPV1 antagonists did not change the frequency of voiding contractions of naïve animals. CB1 antagonist reversed the effect of 0.7 URB while TRPV1 antagonist reduced the effect of 7 URB. AEA levels increase during inflammation. Treating LPS-inflamed animals with 0.7 mg URB brought AEA levels to control levels. Treating LPS-inflamed animals with 7 mg URB did not change AEA levels, compared to LPS-inflamed animals. PEA levels decrease during inflammation. Treating LPS-inflamed animals with 0.7 mg URB brought AEA levels to control levels. Treating LPS-inflamed animals with 7 mg URB, decreased PEA levels to values similar to the ones observed in LPS- -inflamed animals. Conclusion: During cystitis, the FAAH inhibitor raises the levels of PEA and reverses the urinary frequency by a CB1 receptor- mediated mechanism. When used in very high doses, the FAAH antagonist raises the levels of AEA and increases the urinary frequency by a TRPV1-dependent mechanism. Therefore, the choice of FAAH inhibitor dosage to be used in the clinics should consider the putative effects over the endocannabinoid levels in the system. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-12-17T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://doi.org/10.24915/aup.34.3-4.14 oai:oai.actaurologicaportuguesa.com:article/14 |
url |
https://doi.org/10.24915/aup.34.3-4.14 |
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oai:oai.actaurologicaportuguesa.com:article/14 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.none.fl_str_mv |
http://www.actaurologicaportuguesa.com/index.php/aup/article/view/14 https://doi.org/10.24915/aup.34.3-4.14 http://www.actaurologicaportuguesa.com/index.php/aup/article/view/14/24 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Associação Portuguesa de Urologia |
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Associação Portuguesa de Urologia |
dc.source.none.fl_str_mv |
Acta Urológica Portuguesa; Vol. 34 No. 3-4 (2017): july-september; october-december; 21-28 Acta Urológica Portuguesa; v. 34 n. 3-4 (2017): julho-setembro; outubro-dezembro; 21-28 2387-0419 2341-4022 reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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