TNFR1/p38αMAPK signaling in Nex + supraspinal neurons regulates estrogen-dependent chronic neuropathic pain

Authors

Kathryn A. Swanson, Department of Biology, Drexel University, Papadakis Integrated Science Building, Philadelphia, PA 19104, USA.
Kayla L. Nguyen, Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Ross Hall, 2300 I (Eye) St NW, Rm.530A, Washington, D.C 20052, USA. Electronic address: kayla.nguyen@gwu.edu.
Shruti Gupta, Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Ross Hall, 2300 I (Eye) St NW, Rm.530A, Washington, D.C 20052, USA.
Jerome Ricard, Department of Biology, Drexel University, Papadakis Integrated Science Building, Philadelphia, PA 19104, USA.
John R. Bethea, Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Ross Hall, 2300 I (Eye) St NW, Rm.530A, Washington, D.C 20052, USA. Electronic address: jrb117@gwu.edu.

Document Type

Journal Article

Publication Date

4-1-2024

Journal

Brain, behavior, and immunity

Volume

119

DOI

10.1016/j.bbi.2024.03.050

Keywords

Mechanical allodynia; Soluble tumor necrosis factor (sTNF); Supraspinal excitatory projection neurons; TNF receptor 1 (TNFR1); chronic neuropathic pain (CNP); estrogen receptor beta (ER β); p38 mitogen-activated protein kinase (p38MAPK)

Abstract

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 (NexCre::TNFR1). 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-κB, important in TNFR1 signaling and injury response. We detected p38MAPK and NF-κB activation in male cortical tissue; however, p38MAPK phosphorylation was reduced in NexCre::TNFR1 males. We observed a similar recovery from acute pain in male mice following CCI when p38αMAPK was knocked out of supraspinal Nex + neurons (NexCre::p38αMAPK), 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 β (ER β) 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/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.

APA Citation

Swanson, Kathryn A.; Nguyen, Kayla L.; Gupta, Shruti; Ricard, Jerome; and Bethea, John R., "TNFR1/p38αMAPK signaling in Nex + supraspinal neurons regulates estrogen-dependent chronic neuropathic pain" (2024). GW Authored Works. Paper 4793.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4793

Department

Anatomy and Regenerative Biology