FIGURE 1.

Postulated role of P2X4 signaling in chronic pain. Peripheral nerve injury (PNI) activates microglia in the dorsal horn of the spinal cord. This causes the upregulation of the P2X4 expression which is modulated by fibronectin and chemokine ligand 21 (CCL21). CCL2 signaling promotes P2X4 trafficking to cell surface of microglia. Influx of Ca²⁺ through ATP-stimulated P2X4 activates p38-MAPK and drives the synthesis and SNARE-dependent release of brain-derived neurotrophic factor (BDNF). After BDNF is released, it acts on its cognate receptor, trkB which consequently downregulates potassium-chloride cotransporter KCC2 expression in dorsal horn spinal lamina 1 neurons. This results in increase of intracellular [CI^-] and leads to the reduction in anion gradient in dorsal horn which in turn induces depolarization of these neurons. The altered chloride gradient causes GABA to switch its effects from inhibition to excitation. The resultant hyperexcitability in the dorsal horn could underlie the increased sensitivity that is a feature of neuropathic pain.