1. Neurobiologie Cellulaire, Centre de recherche Université Laval Robert-Giffard, Québec, Québec G1J 2G3, Canada
2. Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada

Correspondence to: Yves De Koninck^1,2 Email: Yves.DeKoninck@crulrg.ulaval.ca

Abstract

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 controversial^{3, 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.