Figure 3.

Schematic representation of signal transduction in spinal microglia after nerve injury. (a) Activation of microglial receptors after nerve injury. Peripheral nerve injury generates spontaneous activity (step-1) leading to the release of chemokines (e.g. MCP-1) from primary sensory DRG neurons (step-2). MCP-1 will activate CCR2 receptors on microglia (step-3). Spontaneous activity may also release the proteinases, leading to the cleavage of the chemokine FKN (step-5). After its cleavage from the membrane, FKN will be released to bind CX3CR1 receptor on microglia (step-6). Proteinases may also cleave the precursors of the cytokines TNFα and IL-1β, leading to the activation of TNFα and IL-1β receptors on microglia (step-7). Nerve injury will further release ATP (step-8), activating P2X4 and P2X7 receptors on microglia (step-9). (b) p38 activation in spinal microglia and downstream signaling of p38. Activation of GPCR, or cytokine receptors, or P2X receptors results in p38 MAPK activation in spinal microglia (step-10). p38 activation results in increased expression, through the transcription factor NF-κB (step-11) or other transcription factors (e.g. ATF-2), of secreted inflammatory mediators/growth factors (e.g., cytokines and BDNF, step-12) or of genes encoding membrane receptors (step-13). In addition, p38 also induces release of PGE2 and IL-1β via rapid posttranslational regulation (step-14). Upon release, these mediators will sensitize nociceptive dorsal horn neurons via presynaptic and postsynaptic mechanisms, leading to persistent pain hypersensitivity (step-15). Abbreviations used in Fig 3: BDNF, brain-derived neurotrophic factor; CatS, cysteine protease cathepsin S; DRG, dorsal root ganglion; FKN, fractalkine; GPCR, G-protein coupled receptor; IL-1β, interleukin-1beta; MAPK, mitogen-activated protein kinase; MAPKAP2: MAPK-activated protein kinase-2; PLA2, phospholipase A2; TNFα, tumor necrosis factor-alpha

Ji and Suter Molecular Pain 2007 3:33   doi:10.1186/1744-8069-3-33
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