查看文章

Loss of synaptic inhibition by γ-aminobutyric acid and glycine due to potassium chloride cotransporter-2 (KCC2) down-regulation in the spinal cord is a critical mechanism of synaptic plasticity in neuropathic pain. Here we present novel evidence that peripheral nerve injury diminishes glycine-mediated inhibition and induces a depolarizing shift in the reversal potential of glycine-mediated currents (E_glycine) in spinal dorsal horn neurons. Blocking glutamate N-methyl-d-aspartate (NMDA) receptors normalizes synaptic inhibition, E_glycine, and KCC2 by nerve injury. Strikingly, nerve injury increases calcium-dependent calpain activity in the spinal cord that in turn causes KCC2 cleavage at the C terminus. Inhibiting calpain blocks KCC2 cleavage induced by nerve injury and NMDA, thereby normalizing E_glycine. Furthermore, calpain inhibition or silencing of μ-calpain at the spinal level reduces neuropathic pain. Thus …