The known knowns of microglia–neuronal signalling in neuropathic pain

• Microglial–neuronal interactions are critical in peripheral neuropathic pain.
• The adoption of a reactive phenotype characterized by the surface expression of P2X4 receptors in spinal microglia is necessary.
• P2X4R-p38-BDNF-KCC2 is the core signalling pathway.
• Mediators of each component of the core pathway may represent therapeutic targets for novel analgesics.

Microglia are key cellular mediators of plasticity in the spinal cord that drives the development and maintenance of pain hypersensitivity following peripheral nerve damage. An essential reactive microglial phenotype is characterized by induced expression of purinergic P2X4 receptors. Activation of these receptors initiates a core microglial-neuronal signalling pathway which through disinhibition transforms the output of dorsal horn neurons projecting to the brain pain networks. Here we describe recent advances in elucidating molecules that regulate key aspects of this core pathway, and opportunities for targeting critical signalling hubs to treat neuropathic pain.