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

Kathryn A Swanson; Kayla L Nguyen; Shruti Gupta; Jerome Ricard; John R Bethea

doi:10.1016/j.bbi.2024.03.050

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

Brain Behav Immun. 2024 Apr 1:119:261-271. doi: 10.1016/j.bbi.2024.03.050. Online ahead of print.

Authors

Kathryn A Swanson¹, Kayla L Nguyen², Shruti Gupta³, Jerome Ricard¹, John R Bethea⁴

Affiliations

¹ Department of Biology, Drexel University, Papadakis Integrated Science Building, Philadelphia, PA 19104, USA.
² 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.
³ 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.
⁴ 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.

PMID: 38570102
DOI: 10.1016/j.bbi.2024.03.050

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^ERT2::TNFR1^f/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-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^ERT2::TNFR1^f/f males. We observed a similar recovery from acute pain in male mice following CCI when p38αMAPK was knocked out of supraspinal Nex + neurons (NexCre^ERT2::p38αMAPK^f/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 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.

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).