Abstract Chronic neuropathic pain (CNP) is a maladaptive pathological process that is poorly understood and a condition for which no effective therapies exist. It is largely recognized that neuroinflammation significantly contributes to the development of chronic pain, however the mechanisms are not well understood. A unifying mechanism through which pathological inflammation contributes to the development of chronic pain is by being a key mediator of neuropathology and maladaptive plasticity in brain regions critical for processing somatosensory information such as the somatosensory cortex (S1). The overarching hypothesis to be tested in this competitive renewal is that strategies designed to mitigate pathological neuroinflammation will be therapeutic for spinal cord injury (SCI)-Pain by promoting neurorepair and reducing maladaptive supraspinal plasticity. The studies proposed in this application are based upon extensive published and preliminary data demonstrating diverging roles for TNFR (TNFR1 and TNFR2) signaling and sex differences in the development and resolution of CNP in SCI and peripheral nerve injury (CCI) models. The overarching goals of our competitive renewal are to better understand mechanisms of CNP and to develop therapies that are effective in both women and men. The lack of understanding of neuron-immune cell interactions that lead to the development or resolution of chronic pain is the overarching scientific premise to this application. Our scientific premise and hypotheses will be tested in the following Specific Aims. Specific Aim1: Interrogate the mechanisms through which TNFR2 signaling mitigates neuroinflammation in CNP in males and females. Specific Aim 2: Interrogate the divergent roles for TNFR signaling in the development and resolution of CNP and maladaptive plasticity in males and females. Specific Aim 3: Interrogate the intersection between TNFR1 and ERβ in females and mechanisms whereby inhibiting ERβ in females renders them “male-like” with respect to therapies for CNP.