Poster Session 2 - B12
1-3Josiane C.S. Mapplebeck, 4Louis-Etienne Lorenzo, 1Kwan Lee, 4,5Yves De Koninck, 1-3,6Steve A. Prescott, 1-3.Michael W. Salter
1 Program in Neuroscience & Mental Health, Hospital for Sick Children, Canada; 2 Department of Physiology, University of Toronto, Canada; 3 University of Toronto Centre for the Study of Pain, Canada; 4 Quebec Mental Health Institute Research Center, Canada; 5 Department of Psychiatry and Neuroscience, Université Laval, Canada; 6 Institute of Biomaterials and Biomedical Engineering, University of Toronto, Canada
Peripheral nerve injury (PNI) results in the development of pain hypersensitivity which is similar between males and females. However, the underlying signaling mechanisms are sexually dimorphic: pain hypersensitivity is microglial dependent in males but not in females. Yet, the commonality in pain behavior suggests that signaling downstream of microglia may be convergent between the sexes, which would indicate that pain signaling is degenerate. We investigated this issue by determining whether KCC2, a potassium chloride cotransporter downregulated after nerve injury in males via microglia signaling, is involved in mediating pain hypersensitivity in females. We assessed the involvement of KCC2 in synaptic inhibition in the spinal cord using in vivo electrophysiology. We quantified downregulation of KCC2 using immunohistochemistry. We investigated the role of KCC2 in pain hypersensitivity using intrathecal CLP290 (KCC2 activator) and von Frey measurement of mechanical thresholds. First, we found that inhibiting KCC2 in vivo in naïve animals amplifies evoked firing of dorsal horn neurons in both sexes. Second, we showed that restoration of the Cl- gradient reverses PNI-induced spinal hyperexcitability in males and females. Third, we demonstrated that KCC2 is downregulated after PNI in both sexes. Finally, we found that pain hypersensitivity is equally dependent on KCC2 in male and females. Together, our data indicates that despite sexually dimorphic upstream signaling, KCC2 is uniquely responsible for mediating pain hypersensitivity in both sexes. These findings suggest that neuropathic pain signaling is degenerate. We propose KCC2 as a target for neuropathic pain treatment which circumvents degenerate regulation.