Figure 1.

The different roles of CCL2 and CCL21 in the development of neuropathic pain. Both chemokines are induced in DRG neurons in response to nerve injury. CCL2 in the injured DRG may act as local autocrine signal (neuron-neuron signal) and potentially paracrine in the spinal cord where neuronally released CCL2 may stimulate second order neurons in the pain cascade and/or attract CCR2-expressing peripheral monocytes/macrophages. Since there are conflicting data about the transport of CCL2 from the DRG into the spinal cord, alternatively CCL2 from astrocytes might also activate these target cells. Neuronal CCL21 is transported from the DRG into the spinal cord and contributes to neuron-microglia signaling. CCL21 is the crucial trigger to up-regulate P2X4 receptors in spinal cord microglia which is a vital step in the cascade that leads to neuropathic pain. Although the receptor for CCL21 in spinal cord microglia is an unsolved issue, this chemokine most likely acts as neuron-microglia signal only, since effects of CCL21 in other cells of the spinal cord have yet not been described.