Fig. (1).

Role of Cation Chloride Cotransporters in regulation of Cl⁻ gradients and flux. Cation-chloride cotransporters are responsible for setting the reversal potential for GABA-A or glycine receptor channels. In adult dorsal horn neurons, the anion reversal potential is maintained hyperpolarizing due to Cl⁻ extrusion via KCC2. Trans-synaptic loss of KCC2 expression following peripheral nerve injury causes an intracellular Cl⁻ accumulation which inverts the anion flux upon GABA-A or glycine receptor activation, and thus reverses their action. In primary afferents, GABA-A receptor activation is already depolarizing due to a slightly depolarizing Cl⁻ reversal potential, maintained by the lack of KCC2 expression and by a weak NKCC1 expression. This depolarization remains inhibitory by causing Na⁺ channel inactivation and decreasing Ca⁺⁺ influx upon action potential invasion in the terminal. Following acute inflammation, upregulation or enhanced activity of NKCC1 causes further accumulation of intracellular Cl⁻ which produces an enhanced GABA-A receptor-mediated depolarization that can trigger action potentials effectively converting presynaptic inhibition into cross excitation between afferents.