Chloride Dysregulation through Downregulation of KCC2 Mediates Neuropathic Pain in Both Sexes
Josiane C.S. Mapplebeck,
Louis-Etienne Lorenzo,
Kwan Yeop Lee,
Cédric Gauthier,
Milind M. Muley,
Yves De Koninck,
Steven A. Prescott,
Michael W. Salter
Affiliations
Josiane C.S. Mapplebeck
Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada; University of Toronto Centre for the Study of Pain, Toronto, ON, Canada
Louis-Etienne Lorenzo
CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec, QC, Canada
Kwan Yeop Lee
Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
Cédric Gauthier
CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec, QC, Canada
Milind M. Muley
Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada; University of Toronto Centre for the Study of Pain, Toronto, ON, Canada
Yves De Koninck
CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec, QC, Canada; Department of Psychiatry and Neuroscience, Université Laval, Quebec, QC, Canada
Steven A. Prescott
Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada; University of Toronto Centre for the Study of Pain, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON Canada
Michael W. Salter
Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada; University of Toronto Centre for the Study of Pain, Toronto, ON, Canada; Corresponding author
Summary: The behavioral features of neuropathic pain are not sexually dimorphic despite sex differences in the underlying neuroimmune signaling. This raises questions about whether neural processing is comparably altered. Here, we test whether the K+-Cl− co-transporter KCC2, which regulates synaptic inhibition, plays an equally important role in development of neuropathic pain in male and female rodents. Past studies on KCC2 tested only males. We find that inhibiting KCC2 in uninjured animals reproduces behavioral and electrophysiological features of neuropathic pain in both sexes and, consistent with equivalent injury-induced downregulation of KCC2, that counteracting chloride dysregulation reverses injury-induced behavioral and electrophysiological changes in both sexes. These findings demonstrate that KCC2 downregulation contributes equally to pain hypersensitivity in males and females. Whereas diverse (and sexually dimorphic) mechanisms regulate KCC2, regulation of intracellular chloride relies almost exclusively on KCC2. Directly targeting KCC2 thus remains a promising strategy for treatment of neuropathic pain in both sexes. : Neuropathic pain arises in males and females through distinct neuroimmune signaling. Yet the behavioral (or clinical) features of neuropathic pain are not sexually dimorphic. Mapplebeck et al. demonstrate that KCC2—though regulated in multiple, sex-specific ways—is uniquely responsible for the synaptic disinhibition causing neuropathic pain in both sexes. Keywords: K+-Cl− co-transporter KCC2, sex differences, degeneracy, neuropathic pain, disinhibition, GABA, glycine, BDNF
