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TNFR1/p38αMAPK signaling in Nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain
Upregulation of soluble tumor necrosis factor (sTNF) cytokine signaling through TNF receptor 1 (TNFR1) and subsequent neuronal hyperexcitability are observed in both animal models and human chronic neuropathic pain (CNP) [1–4]. To test the hypothesis that supraspinal circuitry is critical to pain ch...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Journal Experts
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10479400/ https://www.ncbi.nlm.nih.gov/pubmed/37674712 http://dx.doi.org/10.21203/rs.3.rs-3273237/v1 |
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author | Swanson, Kathryn A. Nguyen, Kayla L. Gupta, Shruti Ricard, Jerome Bethea, John R. |
author_facet | Swanson, Kathryn A. Nguyen, Kayla L. Gupta, Shruti Ricard, Jerome Bethea, John R. |
author_sort | Swanson, Kathryn A. |
collection | PubMed |
description | Upregulation of soluble tumor necrosis factor (sTNF) cytokine signaling through TNF receptor 1 (TNFR1) and subsequent neuronal hyperexcitability are observed in both animal models and human chronic neuropathic pain (CNP) [1–4]. To test the hypothesis that supraspinal circuitry is critical to pain chronification, we studied the intersect between supraspinal TNFR1 mediated neuronal signaling and sex specificity by selectively removing TNFR1 in Nex + neurons in adult mice (NexCre(ERT2)::TNFR1(f/f)). We determined that following chronic constriction injury (CCI), pain resolves in males; however, female acute pain transitions to chronic. Subsequently, we investigated two downstream pathways, p38MAPK and NF-κB, important in TNFR1 signaling and injury response. We detected p38αMAPK and NF-κB activation in male cortical tissue; however, p38αMAPK phosphorylation was reduced in NexCre(ERT2)::TNFR1(f/f) males. We observed similar behavioral results following CCI in NexCre(ERT2)::p38αMAPK(f/f) mice. Previously, we established estrogen’s ability to modulate sTNF/TNFR1 signaling in CNP, which may contribute to female prevalence of CNP [5–9]. To explore the intersection between estrogen and inflammation in CNP we used a combination therapy of an estrogen receptor β (ER β) inhibitor with a sTNF/TNFR1 or general p38MAPK inhibitor. We determined both combination therapies lend “male-like” therapeutic relief to females following CCI. These data suggest that TNFR1/p38αMAPK signaling in Nex + neurons in CNP is male-specific and lack of therapeutic efficacy following sTNF inhibition in females is due to ER β interference. These studies highlight sex-specific differences in pathways important to pain chronification and elucidate potential therapeutic strategies that would be effective in both sexes. |
format | Online Article Text |
id | pubmed-10479400 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Journal Experts |
record_format | MEDLINE/PubMed |
spelling | pubmed-104794002023-09-06 TNFR1/p38αMAPK signaling in Nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain Swanson, Kathryn A. Nguyen, Kayla L. Gupta, Shruti Ricard, Jerome Bethea, John R. Res Sq Article Upregulation of soluble tumor necrosis factor (sTNF) cytokine signaling through TNF receptor 1 (TNFR1) and subsequent neuronal hyperexcitability are observed in both animal models and human chronic neuropathic pain (CNP) [1–4]. To test the hypothesis that supraspinal circuitry is critical to pain chronification, we studied the intersect between supraspinal TNFR1 mediated neuronal signaling and sex specificity by selectively removing TNFR1 in Nex + neurons in adult mice (NexCre(ERT2)::TNFR1(f/f)). We determined that following chronic constriction injury (CCI), pain resolves in males; however, female acute pain transitions to chronic. Subsequently, we investigated two downstream pathways, p38MAPK and NF-κB, important in TNFR1 signaling and injury response. We detected p38αMAPK and NF-κB activation in male cortical tissue; however, p38αMAPK phosphorylation was reduced in NexCre(ERT2)::TNFR1(f/f) males. We observed similar behavioral results following CCI in NexCre(ERT2)::p38αMAPK(f/f) mice. Previously, we established estrogen’s ability to modulate sTNF/TNFR1 signaling in CNP, which may contribute to female prevalence of CNP [5–9]. To explore the intersection between estrogen and inflammation in CNP we used a combination therapy of an estrogen receptor β (ER β) inhibitor with a sTNF/TNFR1 or general p38MAPK inhibitor. We determined both combination therapies lend “male-like” therapeutic relief to females following CCI. These data suggest that TNFR1/p38αMAPK signaling in Nex + neurons in CNP is male-specific and lack of therapeutic efficacy following sTNF inhibition in females is due to ER β interference. These studies highlight sex-specific differences in pathways important to pain chronification and elucidate potential therapeutic strategies that would be effective in both sexes. American Journal Experts 2023-08-24 /pmc/articles/PMC10479400/ /pubmed/37674712 http://dx.doi.org/10.21203/rs.3.rs-3273237/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. |
spellingShingle | Article Swanson, Kathryn A. Nguyen, Kayla L. Gupta, Shruti Ricard, Jerome Bethea, John R. TNFR1/p38αMAPK signaling in Nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain |
title | TNFR1/p38αMAPK signaling in Nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain |
title_full | TNFR1/p38αMAPK signaling in Nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain |
title_fullStr | TNFR1/p38αMAPK signaling in Nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain |
title_full_unstemmed | TNFR1/p38αMAPK signaling in Nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain |
title_short | TNFR1/p38αMAPK signaling in Nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain |
title_sort | tnfr1/p38αmapk signaling in nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10479400/ https://www.ncbi.nlm.nih.gov/pubmed/37674712 http://dx.doi.org/10.21203/rs.3.rs-3273237/v1 |
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