Figure 3From: p38 MAPK, microglial signaling, and neuropathic pain 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-alphaBack to article page