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 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.