Figure 1.

Schematic illustration of the potential mechanisms by which P2X4R in activated microglia modulate pain signaling in the dorsal horn after PNI. Nerve injury activates microglia in the dorsal horn of the spinal cord. Activated microglia show increased expression of P2X4R. The upregulation of microglial P2X4R expression involves signaling by fibronectin and chemokine (C-C motif) ligand 21 (CCL21). CCL2 signaling promotes P2X4R trafficking to cell surface of microglia. P2X4R is activated by ATP and, in turn, release bioactive diffusible factors, such as BDNF. BDNF downregulates the potassium-chloride transporter KCC2 via TrkB, causes an increase in intracellular [Cl^-], and leads to the collapse of the transmembrane anion gradient in dorsal horn neurons which in turn induces depolarization of these neurons following stimulation by GABA and glycine. The resultant hyperexcitability in the dorsal horn pain network induced by factors from activated microglia may be responsible for neuropathic pain.