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Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain


Modern pain-control theory1 predicts that a loss of inhibition (disinhibition) in the dorsal horn of the spinal cord is a crucial substrate for chronic pain syndromes2. However, the nature of the mechanisms that underlie such disinhibition has remained controversial3,4,5,6. Here we present evidence for a novel mechanism of disinhibition following peripheral nerve injury. It involves a trans-synaptic reduction in the expression of the potassium–chloride exporter KCC2, and the consequent disruption of anion homeostasis in neurons of lamina I of the superficial dorsal horn, one of the main spinal nociceptive output pathways7. In our experiments, the resulting shift in the transmembrane anion gradient caused normally inhibitory anionic synaptic currents to be excitatory, substantially driving up the net excitability of lamina I neurons. Local blockade or knock-down of the spinal KCC2 exporter in intact rats markedly reduced the nociceptive threshold, confirming that the reported disruption of anion homeostasis in lamina I neurons was sufficient to cause neuropathic pain.

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Figure 1: PNI induced a collapse of anion in LI neurons in the ipsilateral SDH.
Figure 2: Switch from GlyR-only to mixed GABAA-receptor and GlyR-mediated mPSCs following PNI in LI neurons.
Figure 3: PNI-induced downregulation of KCC2 in SDH LI neurons ipsilateral to PNI led to GlyR/GABAA-receptor-mediated excitation.
Figure 4: Selective blockade or knock-down of the postsynaptic KCC2 exporter in the SDH significantly reduced nociceptive threshold.

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Supported by Canadian Institutes of Health Research (CIHR) grants to Y.D.K. and A.S., and a grant from the Burroughs Wellcome Fund (BWF) to P.D.K. J.A.M.C. is the recipient of a CIHR doctoral award. P.D.K. is the recipient of a career award from the BWF. Y.D.K. and A.S. are scholars of the Fonds de la recherche en santé du Québec (FRSQ). We thank C. M. Cahill for help with some of the Ca2+ measurements, L. Pellegrini for advice on the quantification of immunoblotting, and O. Szalay for technical assistance. We also thank F. J. Alvarez, M. Deschênes, P. Drapeau and M. W. Salter for critical comments on the manuscript.

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Correspondence to Yves De Koninck.

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Coull, J., Boudreau, D., Bachand, K. et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424, 938–942 (2003).

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