Fig. 1.

Different activation states of glia. Glia exhibit different activation states after painful injuries. (1) Glial reaction refers to upregulation of glial markers and morphological changes of glia (gliosis); (2) upregulation of glial receptors such as adenosine triphosphate (ATP) receptors, chemokine receptors, and Toll-like receptors, which will lead to the third activation state: (3) activation of intracellular signaling pathways, such as mitogen-activated protein kinase (MAPK) pathways. Phosphorylation of MAPKs will lead to the next activation state: (4) upregulation of glial mediators, such as cytokines, chemokines, and growth factors. Upon release, these glial mediators can interact with neurons to elicit pain via central and peripheral sensitization. Unlike glial reaction (state 1), the other activation states (states 2-4) have been shown to induce pain.