p38 MAPK, microglial signaling, and neuropathic pain - PubMed (original) (raw)

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p38 MAPK, microglial signaling, and neuropathic pain

Ru-Rong Ji et al. Mol Pain. 2007.

Abstract

Accumulating evidence over last several years indicates an important role of microglial cells in the pathogenesis of neuropathic pain. Signal transduction in microglia under chronic pain states has begun to be revealed. We will review the evidence that p38 MAPK is activated in spinal microglia after nerve injury and contributes importantly to neuropathic pain development and maintenance. We will discuss the upstream mechanisms causing p38 activation in spinal microglia after nerve injury. We will also discuss the downstream mechanisms by which p38 produces inflammatory mediators. Taken together, current data suggest that p38 plays a critical role in microglial signaling under neuropathic pain conditions and represents a valuable therapeutic target for neuropathic pain management.

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Figures

Figure 1

Figure 1

Ligation of L5-spinal nerve (SNL) induces p38 activation in microglial cells in the spinal cord. (a) Immunostaining of phosphorylated p38 (p-p38) in the spinal cord 3 days after SNL. Dotted line indicates the outline of the spinal cord gray matter. Modified from [34]. (b) p38 kinase assay reveals that SNL increases the phosphorylation of the p38 substrate ATF-2, suggesting an increase in p38 activity. To perform kinase assay, p-p38 was first immunoprecipitated with a p-p38 antibody, then ATF-2 fusion protein was added. Finally, pATF-2 level was detected using Western blotting with a pATF-2 antibody. (c-e) Double immunofluorescence indicates that p-p38 is not colocalized with NeuN, a neuronal marker (c) and GFAP, an astroglial marker (d), but colocalized with OX-42 (CD11b), a microglial marker (e). Modified from [34].

Figure 2

Figure 2

(a) Reversal of tactile allodynia by p38 inhibition after spinal nerve ligation (SNL) on mice. The p38 inhibitor FR167653 was injected (i.p., 50 mg/kg, in 10% DMSO) at 10 days after SNL. The same injection was repeated daily for additional 4 days (indicated with small arrows). SNL-induced mechanical allodynia was tested at 1 h, 3 h, 6 h, and 1 d after the first injection, then daily for another 6 days. Mean ± SEM (n = 5). Note that p38 inhibitor is still effective in reversing neuropathic pain. Interestingly, the effect is maintained for 2 more days after the last injection. (b) Inhibition of SNL-induced IL-1β upregulation in the spinal cord by p38 inhibition. ELISA shows that intrathecal injection of the p38 inhibitor SB203580 (10 μg, twice a day for 3 days) reduces SNL-induced IL-1β increase in the L5 spinal cord (dorsal part) 3 days after SNL (L5). **, P < 0.01, compared to Sham; +, P < 0.05, compared to SNL, ANOVA.

Figure 3

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

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