Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.ynpai.2020.100049 http://hdl.handle.net/11449/198935 |
Resumo: | Though sex differences in chronic pain have been consistently described in the literature, their underlying neural mechanisms are poorly understood. Previous work in humans has demonstrated that men and women differentially invoke distinct brain regions and circuits in coping with subjective pain unpleasantness. The goal of the present work was to elucidate the molecular mechanisms in the basolateral nucleus of the amygdala (BLA) that modulate hyperalgesic priming, a pain plasticity model, in males and females. We used plantar incision as the first, priming stimulus and prostaglandin E2 (PGE2) as the second stimulus. We sought to assess whether hyperalgesic priming can be prevented or reversed by pharmacologically manipulating molecular targets in the BLA of male or female mice. We found that administering ZIP, a cell-permeable inhibitor of aPKC, into the BLA attenuated aspects of hyperalgesic priming induced by plantar incision in males and females. However, incision only upregulated PKCζ/PKMζ immunoreactivity in the BLA of male mice, and deficits in hyperalgesic priming were seen only when we restricted our analysis to male Prkcz−/− mice. On the other hand, intra-BLA microinjections of pep2m, a peptide that interferes with the trafficking and function of GluA2-containing AMPA receptors, a downstream target of aPKC, reduced mechanical hypersensitivity after plantar incision and disrupted the development of hyperalgesic priming in both male and female mice. In addition, pep2m treatment reduced facial grimacing and restored aberrant behavioral responses in the sucrose splash test in male and female primed mice. Immunofluorescence results demonstrated upregulation of GluA2 expression in the BLA of male and female primed mice, consistent with pep2m findings. We conclude that, in a model of incision-induced hyperalgesic priming, PKCζ/PKMζ in the BLA is critical for the development of hyperalgesic priming in males, while GluA2 in the BLA is crucial for the expression of both reflexive and affective pain-related behaviors in both male and female mice in this model. Our findings add to a growing body of evidence of sex differences in molecular pain mechanisms in the brain. |
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Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming modelaPKCBasolateral amygdalaGluA2Hyperalgesic primingSex differencesZIPThough sex differences in chronic pain have been consistently described in the literature, their underlying neural mechanisms are poorly understood. Previous work in humans has demonstrated that men and women differentially invoke distinct brain regions and circuits in coping with subjective pain unpleasantness. The goal of the present work was to elucidate the molecular mechanisms in the basolateral nucleus of the amygdala (BLA) that modulate hyperalgesic priming, a pain plasticity model, in males and females. We used plantar incision as the first, priming stimulus and prostaglandin E2 (PGE2) as the second stimulus. We sought to assess whether hyperalgesic priming can be prevented or reversed by pharmacologically manipulating molecular targets in the BLA of male or female mice. We found that administering ZIP, a cell-permeable inhibitor of aPKC, into the BLA attenuated aspects of hyperalgesic priming induced by plantar incision in males and females. However, incision only upregulated PKCζ/PKMζ immunoreactivity in the BLA of male mice, and deficits in hyperalgesic priming were seen only when we restricted our analysis to male Prkcz−/− mice. On the other hand, intra-BLA microinjections of pep2m, a peptide that interferes with the trafficking and function of GluA2-containing AMPA receptors, a downstream target of aPKC, reduced mechanical hypersensitivity after plantar incision and disrupted the development of hyperalgesic priming in both male and female mice. In addition, pep2m treatment reduced facial grimacing and restored aberrant behavioral responses in the sucrose splash test in male and female primed mice. Immunofluorescence results demonstrated upregulation of GluA2 expression in the BLA of male and female primed mice, consistent with pep2m findings. We conclude that, in a model of incision-induced hyperalgesic priming, PKCζ/PKMζ in the BLA is critical for the development of hyperalgesic priming in males, while GluA2 in the BLA is crucial for the expression of both reflexive and affective pain-related behaviors in both male and female mice in this model. Our findings add to a growing body of evidence of sex differences in molecular pain mechanisms in the brain.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Institutes of HealthDept. Psychology Federal University of Sao Carlos-UFSCarUniversity of Texas at Dallas School of Behavioral and Brain Sciences and Center for Advanced Pain StudiesJanssen Research & Development Neuroscience Therapeutic AreaYale University School of Medicine Department of NeurologyJoint Graduate Program in Physiological Sciences UFSCar/UNESPGraduate Program in Psychology UFSCarLab. Pharmacology School of Pharmaceutical Sciences Univ. Estadual Paulista – UNESPJoint Graduate Program in Physiological Sciences UFSCar/UNESPLab. Pharmacology School of Pharmaceutical Sciences Univ. Estadual Paulista – UNESPFAPESP: 2018/04775-0CNPq: 306556/2015-4CNPq: 451500/2013-0National Institutes of Health: NS065926National Institutes of Health: NS115441Universidade Federal de São Carlos (UFSCar)School of Behavioral and Brain Sciences and Center for Advanced Pain StudiesNeuroscience Therapeutic AreaYale University School of MedicineUniversidade Estadual Paulista (Unesp)Baptista-de-Souza, DanielaTavares-Ferreira, DianaMegat, SalimSankaranarayanan, IshwaryaShiers, StephanieFlores, Christopher M.Ghosh, SouravLuiz Nunes-de-Souza, Ricardo [UNESP]Canto-de-Souza, Azair [UNESP]Price, Theodore J.2020-12-12T01:26:00Z2020-12-12T01:26:00Z2020-08-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.ynpai.2020.100049Neurobiology of Pain, v. 8.2452-073Xhttp://hdl.handle.net/11449/19893510.1016/j.ynpai.2020.1000492-s2.0-85085954286Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengNeurobiology of Paininfo:eu-repo/semantics/openAccess2021-10-22T21:03:19Zoai:repositorio.unesp.br:11449/198935Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T19:23:41.247199Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model |
title |
Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model |
spellingShingle |
Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model Baptista-de-Souza, Daniela aPKC Basolateral amygdala GluA2 Hyperalgesic priming Sex differences ZIP |
title_short |
Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model |
title_full |
Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model |
title_fullStr |
Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model |
title_full_unstemmed |
Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model |
title_sort |
Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model |
author |
Baptista-de-Souza, Daniela |
author_facet |
Baptista-de-Souza, Daniela Tavares-Ferreira, Diana Megat, Salim Sankaranarayanan, Ishwarya Shiers, Stephanie Flores, Christopher M. Ghosh, Sourav Luiz Nunes-de-Souza, Ricardo [UNESP] Canto-de-Souza, Azair [UNESP] Price, Theodore J. |
author_role |
author |
author2 |
Tavares-Ferreira, Diana Megat, Salim Sankaranarayanan, Ishwarya Shiers, Stephanie Flores, Christopher M. Ghosh, Sourav Luiz Nunes-de-Souza, Ricardo [UNESP] Canto-de-Souza, Azair [UNESP] Price, Theodore J. |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Federal de São Carlos (UFSCar) School of Behavioral and Brain Sciences and Center for Advanced Pain Studies Neuroscience Therapeutic Area Yale University School of Medicine Universidade Estadual Paulista (Unesp) |
dc.contributor.author.fl_str_mv |
Baptista-de-Souza, Daniela Tavares-Ferreira, Diana Megat, Salim Sankaranarayanan, Ishwarya Shiers, Stephanie Flores, Christopher M. Ghosh, Sourav Luiz Nunes-de-Souza, Ricardo [UNESP] Canto-de-Souza, Azair [UNESP] Price, Theodore J. |
dc.subject.por.fl_str_mv |
aPKC Basolateral amygdala GluA2 Hyperalgesic priming Sex differences ZIP |
topic |
aPKC Basolateral amygdala GluA2 Hyperalgesic priming Sex differences ZIP |
description |
Though sex differences in chronic pain have been consistently described in the literature, their underlying neural mechanisms are poorly understood. Previous work in humans has demonstrated that men and women differentially invoke distinct brain regions and circuits in coping with subjective pain unpleasantness. The goal of the present work was to elucidate the molecular mechanisms in the basolateral nucleus of the amygdala (BLA) that modulate hyperalgesic priming, a pain plasticity model, in males and females. We used plantar incision as the first, priming stimulus and prostaglandin E2 (PGE2) as the second stimulus. We sought to assess whether hyperalgesic priming can be prevented or reversed by pharmacologically manipulating molecular targets in the BLA of male or female mice. We found that administering ZIP, a cell-permeable inhibitor of aPKC, into the BLA attenuated aspects of hyperalgesic priming induced by plantar incision in males and females. However, incision only upregulated PKCζ/PKMζ immunoreactivity in the BLA of male mice, and deficits in hyperalgesic priming were seen only when we restricted our analysis to male Prkcz−/− mice. On the other hand, intra-BLA microinjections of pep2m, a peptide that interferes with the trafficking and function of GluA2-containing AMPA receptors, a downstream target of aPKC, reduced mechanical hypersensitivity after plantar incision and disrupted the development of hyperalgesic priming in both male and female mice. In addition, pep2m treatment reduced facial grimacing and restored aberrant behavioral responses in the sucrose splash test in male and female primed mice. Immunofluorescence results demonstrated upregulation of GluA2 expression in the BLA of male and female primed mice, consistent with pep2m findings. We conclude that, in a model of incision-induced hyperalgesic priming, PKCζ/PKMζ in the BLA is critical for the development of hyperalgesic priming in males, while GluA2 in the BLA is crucial for the expression of both reflexive and affective pain-related behaviors in both male and female mice in this model. Our findings add to a growing body of evidence of sex differences in molecular pain mechanisms in the brain. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-12-12T01:26:00Z 2020-12-12T01:26:00Z 2020-08-01 |
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 |
http://dx.doi.org/10.1016/j.ynpai.2020.100049 Neurobiology of Pain, v. 8. 2452-073X http://hdl.handle.net/11449/198935 10.1016/j.ynpai.2020.100049 2-s2.0-85085954286 |
url |
http://dx.doi.org/10.1016/j.ynpai.2020.100049 http://hdl.handle.net/11449/198935 |
identifier_str_mv |
Neurobiology of Pain, v. 8. 2452-073X 10.1016/j.ynpai.2020.100049 2-s2.0-85085954286 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Neurobiology of Pain |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1808129062315491328 |