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Tumor necrosis factor receptor 1 inhibition is therapeutic for neuropathic pain in males but not in females

del Rivero, Tania; Fischer, Roman; Yang, Fan; Swanson, Kathryn A.; Bethea, John R.*

doi: 10.1097/j.pain.0000000000001470
Research Paper
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Tumor necrosis factor (TNF) is a proinflammatory cytokine, which is involved in physiological and pathological processes and has been found to be crucial for pain development. In the current study, we were interested in the effects of blocking Tumor necrosis factor receptor 1 (TNFR1) signaling on neuropathic pain after peripheral nerve injury with the use of transgenic mice and pharmacological inhibition. We have previously shown that TNFR1−/− mice failed to develop neuropathic pain and depressive symptoms after chronic constriction injury (CCI). To investigate the therapeutic effects of inhibiting TNFR1 signaling after injury, we delivered a drug that inactivates soluble TNF (XPro1595). Inhibition of solTNF signaling resulted in an accelerated recovery from neuropathic pain in males, but not in females. To begin exploring a mechanism, we investigated changes in N-methyl-D-aspartate (NMDA) receptors because neuropathic pain has been shown to invoke an increase in glutamatergic signaling. In male mice, XPro1595 treatment reduces elevated NMDA receptor levels in the brain after injury, whereas in female mice, NMDA receptor levels decrease after CCI. We further show that estrogen inhibits the therapeutic response of XPro1595 in females. Our results suggest that TNFR1 signaling plays an essential role in pain induction after CCI in males but not in females.

This article describes that the TNFR1 in males is essential for pain development, but not in females. Pharmacological neutralization of this pathways is only therapeutic in males, whereas estrogen in females abolishes the therapeutic effect.

Department of Biology, Drexel University, Philadelphia, PA, United States

Corresponding author. Address: Department of Biology, Drexel University, 3245 Chestnut St, Philadelphia, PA 19104, United States. Tel.: +1 215 895 6189. E-mail address: jrb445@drexel.edu (J.R. Bethea).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

T. del Rivero and R. Fischer contributed equally to this work.

All coauthors have contributed substantially to the research and approve the contents of the manuscript. The submission is not under review at any other publication.

Received October 05, 2018

Received in revised form December 05, 2018

Accepted December 09, 2018

© 2019 International Association for the Study of Pain
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