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TNFR1/p38 α MAPK signaling in Nex plus supraspinal neurons regulates estrogen-dependent chronic neuropathic pain
Journal article   Open access   Peer reviewed

TNFR1/p38 α MAPK signaling in Nex plus supraspinal neurons regulates estrogen-dependent chronic neuropathic pain

Kathryn A. Swanson, Kayla L. Nguyen, Shruti Gupta, Jerome Ricard and John R. Bethea
Brain, behavior, and immunity, v 119, pp 261-271
01 Jul 2024
DOI: https://doi.org/10.1016/j.bbi.2024.03.050
PMID: 38570102
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://pmc.ncbi.nlm.nih.gov/articles/PMC11162907/pdf/nihms-1986944.pdfView
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Abstract

Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology Science & Technology Immunology Psychiatry
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). Previously, we have shown that estrogen modulates sTNF/TNFR1 signaling in CNP, which may contribute to female prevalence of CNP. The estrogen-dependent role of TNFR1-mediated supraspinal neuronal circuitry in CNP remains unknown. In this study, we interrogated the intersect between supraspinal TNFR1 mediated neuronal signaling and sex specificity by selectively removing TNFR1 in Nex + neurons in adult mice (NexCreERT2::TNFR1f/f). We determined that mechanical hypersensitivity induced by chronic constriction injury (CCI) decreases over time in males, but not in females. Subsequently, we investigated two downstream pathways, p38MAPK and NF-kappa B, important in TNFR1 signaling and injury response. We detected p38MAPK and NF-kappa B activation in male cortical tissue; however, p38MAPK phosphorylation was reduced in NexCreERT2::TNFR1f/f males. We observed a similar recovery from acute pain in male mice following CCI when p38 alpha MAPK was knocked out of supraspinal Nex + neurons (NexCreERT2::p38 alpha MAPKf/f), while chronic pain developed in female mice. To explore the intersection between estrogen and inflammation in CNP we used a combination therapy of an estrogen receptor beta (ER beta) inhibitor with a sTNF/TNFR1 or general p38MAPK inhibitor. We determined both combination therapies lends therapeutic relief to females following CCI comparable to the response evaluated in male mice. These data suggest that TNFR1/p38 alpha MAPK signaling in Nex + neurons in CNP is male-specific and lack of therapeutic efficacy following sTNF inhibition in females is due to ER beta 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.

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Collaboration types
Domestic collaboration
Web of Science research areas
Immunology
Neurosciences
Psychiatry
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