Fig. 1.

A unified schema for signalling in the superficial spinal dorsal horn in pain hypersensitivity. Peripheral nerve injury drives de novo expression of P2X4Rs in microglia, but only in males, leading to release of BDNF and activation of its cognate receptor, TrkB, on neurons in lamina I. Subsequent intracellular pathways in the neurons downregulate KCC2 and upregulate the function of GluN2B-containing NMDARs by activating Fyn and suppressing STEP61. In females, although microglia proliferation occurs, P2X4R expression does not increase. Nevertheless, KCC2 is downregulated and NMDAR is enhanced in females by signalling molecules and pathways that remain to be identified. Also shown is that BDNF may be released from primary sensory neurons activated by peripheral inflammation