Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticulados
Autor(a) principal: | |
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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/1/24543 |
Resumo: | Morphine, in addition to being an analgesic drug, also has a high additive potential related to neuroadaptations of the dopaminergic and glutamatergic pathways, in addition to the increase in oxidative events in the mesocorticolimbic area, which characterizes drug addiction. The treatments available for this pathology have limitations, as they act only in drug withdrawal, without preventing relapse. Neural functions can be modified by dietary constituents, especially by the type of fatty acid (FA) consumed, the influence of supplementation of fats present in the Mediterranean diet (MD, rich in omega-3) and in Western diets (WDs: palm oil -PO and interesterified fat-IF) on the additive properties of morphine was evaluated. Male rats were submitted to the Conditioned Place Preference (CPP) protocol with morphine (4mg/Kg, i.p.), followed by behavioral assessments of preference, abstinence and drug relapse and subsequent euthanasia for molecular analysis. The consumption of WDs increased parameters of anxiety per se, locomotor sensitization and drug relapse, which was not observed with MD. At the molecular level, the WDs increased the immunoreactivity of the glucocorticoid receptor in the frontal cortex, of the dopamine transporter (DAT) and type 2 dopaminergic receptor (D2R) in the nucleus accumbens (NAc), reducing the immunoreactivity of D1R in the same area. Based on this evidence, it is important to emphasize that the consumption of WDs facilitates morphine reinstatement, which can make opioid detoxification more difficult. It is known that the chronic use of opioids can modify the glutamatergic neurotransmission as well as the hedonia evoked by the increased release of dopamine, favoring the generation of oxidative damage. These data led to the development of two subsequent protocols: evaluation of the glutamatergic antagonist topiramate in its free (S-TPM, 0.5mg/Kg, ip) and nanoescapsulated (TPM-CS-NP, 0.57mg/Kg, ip), and evaluation of the antioxidant ferulic acid, in its free form (F-FA, 0.5mg/Kg, po) and nanoencapsulated (FA-Nc, 0.5mg/Kg, po), against morphine reinstatement. Treatments with TPM-CS-NP and FA-Nc prevented drug relapse, preserving memory, which was impaired by morphine and S-TPM. In the TPM protocol, morphine increased the immunoreactivity of D1R, D2R, D3R, DAT, GluA1 and MOR in NAc and of D1R, DAT, GluA1 and MOR in the dorsal hippocampus, while TPM-CS-NP decreased the levels of D1R, D3R and GluA1 and increased DAT in NAc, decreased GluA1 and increased D2 and DAT in dorsal hippocampus, preventing drug relapse and protecting memory, which indicates the therapeutic superiority of this nanoformulation. In the FA protocol, morphine increased the levels of D1R, D3R, DAT, ΔFosB in the NAc, while the FA-Nc decreased D1R, D3R and ΔFosB and increased D2R, DAT and NRF2 in the NAc, preventing relapse to the drug, indicating a neuroprotective role of this nanoformulation. Morphine drug addiction is multifactorial and can be avoided through a consumption of MD, as well as prevented through treatments with nanoparticles of TPM and FA during abstinence. |
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Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticuladosDopaminergic and glutamatergic modulation in morphine reinstatement in rats: influence of diet and nanoparticulated drugsOpioidesDrogadiçãoDietaTopiramatoÁcido ferúlicoOpioidsDrug addiction dietTopiramateFerulic acidCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAMorphine, in addition to being an analgesic drug, also has a high additive potential related to neuroadaptations of the dopaminergic and glutamatergic pathways, in addition to the increase in oxidative events in the mesocorticolimbic area, which characterizes drug addiction. The treatments available for this pathology have limitations, as they act only in drug withdrawal, without preventing relapse. Neural functions can be modified by dietary constituents, especially by the type of fatty acid (FA) consumed, the influence of supplementation of fats present in the Mediterranean diet (MD, rich in omega-3) and in Western diets (WDs: palm oil -PO and interesterified fat-IF) on the additive properties of morphine was evaluated. Male rats were submitted to the Conditioned Place Preference (CPP) protocol with morphine (4mg/Kg, i.p.), followed by behavioral assessments of preference, abstinence and drug relapse and subsequent euthanasia for molecular analysis. The consumption of WDs increased parameters of anxiety per se, locomotor sensitization and drug relapse, which was not observed with MD. At the molecular level, the WDs increased the immunoreactivity of the glucocorticoid receptor in the frontal cortex, of the dopamine transporter (DAT) and type 2 dopaminergic receptor (D2R) in the nucleus accumbens (NAc), reducing the immunoreactivity of D1R in the same area. Based on this evidence, it is important to emphasize that the consumption of WDs facilitates morphine reinstatement, which can make opioid detoxification more difficult. It is known that the chronic use of opioids can modify the glutamatergic neurotransmission as well as the hedonia evoked by the increased release of dopamine, favoring the generation of oxidative damage. These data led to the development of two subsequent protocols: evaluation of the glutamatergic antagonist topiramate in its free (S-TPM, 0.5mg/Kg, ip) and nanoescapsulated (TPM-CS-NP, 0.57mg/Kg, ip), and evaluation of the antioxidant ferulic acid, in its free form (F-FA, 0.5mg/Kg, po) and nanoencapsulated (FA-Nc, 0.5mg/Kg, po), against morphine reinstatement. Treatments with TPM-CS-NP and FA-Nc prevented drug relapse, preserving memory, which was impaired by morphine and S-TPM. In the TPM protocol, morphine increased the immunoreactivity of D1R, D2R, D3R, DAT, GluA1 and MOR in NAc and of D1R, DAT, GluA1 and MOR in the dorsal hippocampus, while TPM-CS-NP decreased the levels of D1R, D3R and GluA1 and increased DAT in NAc, decreased GluA1 and increased D2 and DAT in dorsal hippocampus, preventing drug relapse and protecting memory, which indicates the therapeutic superiority of this nanoformulation. In the FA protocol, morphine increased the levels of D1R, D3R, DAT, ΔFosB in the NAc, while the FA-Nc decreased D1R, D3R and ΔFosB and increased D2R, DAT and NRF2 in the NAc, preventing relapse to the drug, indicating a neuroprotective role of this nanoformulation. Morphine drug addiction is multifactorial and can be avoided through a consumption of MD, as well as prevented through treatments with nanoparticles of TPM and FA during abstinence.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESA morfina, além de fármaco analgésico também apresenta alto potencial aditivo relacionado à neuroadaptações das vias dopaminérgica e glutamatérgica, além do aumento de eventos oxidativos na área mesocorticolímbica, o que caracteriza a drogadição. Os tratamentos disponíveis para esta patologia apresentam limitações, pois atuam apenas na retirada da droga, sem prevenir a recaída. As funções neurais podem ser modificadas pelos constituintes da dieta, especialmente pelo tipo de ácido graxo (AG) consumido, a influência da suplementação de gorduras presentes na dieta mediterrânea (DM, rica em ômega-3) e nas dietas ocidentais (DOs: óleo de palma-OP e gordura interesterificada-GI) sobre as propriedades aditivas da morfina foi avaliada. Ratos machos foram submetidos ao protocolo de preferência de lugar condicionado (PLC) com morfina (4mg/Kg, i.p.), seguido de avaliações comportamentais de preferência, abstinência e recaída à droga e subsequente eutanásia para análises moleculares. O consumo das DOs aumentou parâmetros de ansiedade per se, sensibilização locomotora e recaída à droga, o que não foi observado com a DM. Em nível molecular, as DOs aumentaram a imunoreatividade do receptor glicocorticóide no córtex-frontal, do transportador de dopamina (DAT) e receptor dopaminérgico tipo 2 (D2R) no núcleo accumbens (NAc), reduzido a imunoreatividade do D1R na mesma área. A partir destas evidências é importante enfatizar que o consumo de DOs facilita comportamentos de recaída à morfina, o que pode dificultar a desintoxicação de opioides. Sabe-se que o uso crônico de opioides pode modificar a neurotransmissão glutamatérgica bem como a hedonia evocada pela maior liberação de dopamina, favorecendo a geração de danos oxidativos. Tais dados conduziram o desenvolvimento de dois protocolos subsequentes: avaliação do antagonista glutamatérgico topiramato em sua forma livre (S-TPM, 0.5mg/Kg, i.p.) e nanoescapsulada (TPM-CS-NP, 0.57mg/Kg, i.p.), e avaliação do antioxidante ácido ferúlico, em sua forma livre (F-FA, 0.5mg/Kg, v.o) e nanoencapsulada (FA-Nc, 0.5mg/Kg, v.o.), frente à recaída à morfina. Tratamentos com TPM-CS-NP e FA-Nc preveniram a recaída à droga, preservando a memória, a qual foi prejudicada pela morfina e pelo S-TPM. No protocolo do TPM, a morfina aumentou a imunorreatividade de D1R, D2R, D3R, DAT, GluA1 e MOR no NAc e de D1R, DAT, GluA1 e MOR no hipocampo dorsal, enquanto o TPM-CS-NP diminuiu os níveis de D1R, D3R e GluA1 e aumentou DAT no NAc, diminuiu GluA1 e aumentou D2 e DAT no hipocampo dorsal, prevenindo a recaída à droga e protegendo a memória, o que indica a superioridade terapêutica desta nanoformulação. No protocolo do AF, a morfina aumentou os níveis de D1R, D3R, DAT, ΔFosB no NAc, enquanto o FA-Nc diminuiu D1R, D3R e ΔFosB e aumentou D2R, DAT e NRF2 no NAc, prevenindo a recaída à droga, indicando um papel neuroprotetor desta nanoformulação. A drogadição por morfina é multifatorial podendo ser evitada através de um consumo de DM, bem como prevenida através de tratamentos com nanoparticulas de TPM e AF durante a abstinência.Universidade Federal de Santa MariaBrasilFarmacologiaUFSMPrograma de Pós-Graduação em FarmacologiaCentro de Ciências da SaúdeBurger, Marilise Escobarhttp://lattes.cnpq.br/9128090974948413Savegnago, LucielliBruning, Cesar AugustoSari, Marcel Henrique MarcondesBochi, Guilherme VargasMilanesi, Laura Hautrive2022-05-27T18:41:10Z2022-05-27T18:41:10Z2021-09-30info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/24543porAttribution-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:UFSM2022-05-27T18:42:13Zoai:repositorio.ufsm.br:1/24543Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2022-05-27T18:42:13Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticulados Dopaminergic and glutamatergic modulation in morphine reinstatement in rats: influence of diet and nanoparticulated drugs |
title |
Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticulados |
spellingShingle |
Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticulados Milanesi, Laura Hautrive Opioides Drogadição Dieta Topiramato Ácido ferúlico Opioids Drug addiction diet Topiramate Ferulic acid CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticulados |
title_full |
Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticulados |
title_fullStr |
Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticulados |
title_full_unstemmed |
Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticulados |
title_sort |
Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticulados |
author |
Milanesi, Laura Hautrive |
author_facet |
Milanesi, Laura Hautrive |
author_role |
author |
dc.contributor.none.fl_str_mv |
Burger, Marilise Escobar http://lattes.cnpq.br/9128090974948413 Savegnago, Lucielli Bruning, Cesar Augusto Sari, Marcel Henrique Marcondes Bochi, Guilherme Vargas |
dc.contributor.author.fl_str_mv |
Milanesi, Laura Hautrive |
dc.subject.por.fl_str_mv |
Opioides Drogadição Dieta Topiramato Ácido ferúlico Opioids Drug addiction diet Topiramate Ferulic acid CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Opioides Drogadição Dieta Topiramato Ácido ferúlico Opioids Drug addiction diet Topiramate Ferulic acid CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Morphine, in addition to being an analgesic drug, also has a high additive potential related to neuroadaptations of the dopaminergic and glutamatergic pathways, in addition to the increase in oxidative events in the mesocorticolimbic area, which characterizes drug addiction. The treatments available for this pathology have limitations, as they act only in drug withdrawal, without preventing relapse. Neural functions can be modified by dietary constituents, especially by the type of fatty acid (FA) consumed, the influence of supplementation of fats present in the Mediterranean diet (MD, rich in omega-3) and in Western diets (WDs: palm oil -PO and interesterified fat-IF) on the additive properties of morphine was evaluated. Male rats were submitted to the Conditioned Place Preference (CPP) protocol with morphine (4mg/Kg, i.p.), followed by behavioral assessments of preference, abstinence and drug relapse and subsequent euthanasia for molecular analysis. The consumption of WDs increased parameters of anxiety per se, locomotor sensitization and drug relapse, which was not observed with MD. At the molecular level, the WDs increased the immunoreactivity of the glucocorticoid receptor in the frontal cortex, of the dopamine transporter (DAT) and type 2 dopaminergic receptor (D2R) in the nucleus accumbens (NAc), reducing the immunoreactivity of D1R in the same area. Based on this evidence, it is important to emphasize that the consumption of WDs facilitates morphine reinstatement, which can make opioid detoxification more difficult. It is known that the chronic use of opioids can modify the glutamatergic neurotransmission as well as the hedonia evoked by the increased release of dopamine, favoring the generation of oxidative damage. These data led to the development of two subsequent protocols: evaluation of the glutamatergic antagonist topiramate in its free (S-TPM, 0.5mg/Kg, ip) and nanoescapsulated (TPM-CS-NP, 0.57mg/Kg, ip), and evaluation of the antioxidant ferulic acid, in its free form (F-FA, 0.5mg/Kg, po) and nanoencapsulated (FA-Nc, 0.5mg/Kg, po), against morphine reinstatement. Treatments with TPM-CS-NP and FA-Nc prevented drug relapse, preserving memory, which was impaired by morphine and S-TPM. In the TPM protocol, morphine increased the immunoreactivity of D1R, D2R, D3R, DAT, GluA1 and MOR in NAc and of D1R, DAT, GluA1 and MOR in the dorsal hippocampus, while TPM-CS-NP decreased the levels of D1R, D3R and GluA1 and increased DAT in NAc, decreased GluA1 and increased D2 and DAT in dorsal hippocampus, preventing drug relapse and protecting memory, which indicates the therapeutic superiority of this nanoformulation. In the FA protocol, morphine increased the levels of D1R, D3R, DAT, ΔFosB in the NAc, while the FA-Nc decreased D1R, D3R and ΔFosB and increased D2R, DAT and NRF2 in the NAc, preventing relapse to the drug, indicating a neuroprotective role of this nanoformulation. Morphine drug addiction is multifactorial and can be avoided through a consumption of MD, as well as prevented through treatments with nanoparticles of TPM and FA during abstinence. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-09-30 2022-05-27T18:41:10Z 2022-05-27T18:41:10Z |
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/1/24543 |
url |
http://repositorio.ufsm.br/handle/1/24543 |
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 Farmacologia UFSM Programa de Pós-Graduação em Farmacologia Centro de Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Farmacologia Centro de Ciências da Saúde |
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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1805922173239427072 |