Glia
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Activation of macrophages/microglia via toll-like receptors (TLRs) plays an important role in inflammation and host defense against pathogens. Pathogen-associated molecular patterns bind TLRs, thereby triggering NF-κB signaling and production of proinflammatory cytokines. Recent data suggest that nonpathogenic molecules resulting from trauma can also trigger inflammation via TLRs. ⋯ Paw withdrawal threshold and latency in response to mechanical and heat stimuli, respectively, decreased shortly after nerve lesion in wild type mice. In TLR2 KO mice, nerve injury-induced thermal hyperalgesia was completely abolished contrary to that seen in wild-type mice, whereas mechanical allodynia was partially reduced. We suggest that TLR2 is necessary for the development of neuropathic pain and its contribution is more important in thermal hypersensitivity than that of mechanical allodynia.
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Neuropathic pain produced by damage to or dysfunction of the nervous system is a common and severely disabling state that affects millions of people worldwide. Recent evidence indicates that activated microglia are key cellular intermediaries in the pathogenesis of neuropathic pain and that ATP serves as the mediator. However, the in vivo mechanism underlying the retention of activated microglia in the injured region has not yet been completely elucidated. ⋯ The intrathecal injection of indomethacin, a nonsteroidal anti-inflammatory drug, ONO-8713, a selective EP1 antagonist, or 7-nitroindole, a neuronal NO synthase inhibitor, attenuated mechanical allodynia and the increase in activated microglia observed in the established neuropathic-pain state. We further demonstrated that ATP-induced microglial migration was blocked in vitro by PGE(2) via EP2 and by S-nitrosoglutathione, an NO donor. Taken together, the present study suggests that PGE(2) participated in the maintenance of neuropathic pain in vivo not only by activating spinal neurons, but also by retaining microglia in the central terminals of primary afferent fibers via EP2 subtype and via EP1-mediated NO production.