Sex Differences in Neuropathic Pain and the Role of TNF Signaling

Neuropathic pain is a chronic type of pain caused by damage to the nervous system. Over time the pain tends to intensify, interrupting the daily lives of those affected, and can lead to increases in anxiety and depression. Treatments for neuropathic pain are often ineffective or have severe side effects. Recent studies have focused on targeting pro-inflammatory cytokines such as tumor necrosis factor (TNF) for neuropathic pain treatment due to the involvement of the immune response in pain propagation. Females in general tend to suffer more from pain, yet surprisingly pain studies performed in mouse models predominantly use male mice. In our study we used both male and female mice to characterize sex differences in pain mechanisms and to analyze the role of TNF in neuropathic pain. We establish that TNF Receptor 1 (TNFR1) inhibition reduces pain in males, and ovariectomized females, but not in gonadally-intact females, and this effect is likely mediated by NMDA receptors. Other sexually dimorphic pain characteristics include sex specific changes in levels of presynaptic protein synaptophysin and postsynaptic protein PSD95. To further outline the role of TNF in neuropathic pain we investigated the expression levels of two main TNF receptors, TNFR1 and TNFR2, and the effects of central TNFR1 signaling on pain. Here we demonstrate peripheral TNFR1 signaling as well as TNFR1 signaling within the nervous system are both involved in pain induction. Our data suggests TNFR2 signaling does not play a major role in pain, but may play a role in recovery since receptor levels are reduced following injury and ligand levels increase immediately prior to pain extinction.Ph.D., Biological Sciences -- Drexel University, 201