title: The direction of synaptic plasticity mediated by C-fibers in spinal dorsal horn is decided by Src-family kinases in microglia: the role of tumor necrosis factor-alpha.
abstract: Previous studies have shown that Src-family kinases (SFKs) are selectively activated in spinal microglia following peripheral nerve injury and the activated SFKs play a key role for the development of neuropathic pain. To investigate the underlying mechanism, in the present study the effect of SFKs on long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, which is believed as central mechanism of neuropathic pain, was investigated in adult rats. Electrophysiological data revealed that pretreatment with either microglia inhibitor (minocycline, 200 microM) or SFKs inhibitors (PP2, 100 microM and SU6656, 200 microM) reversed the effect of high frequency stimulation (HFS), that is, HFS, which induces long-term potentiation (LTP) normally, induced long-term depression (LTD) after inhibition of either microglia or SFKs. Western blotting analysis showed that the level of phosphorylated SFKs (p-SFKs) in ipsilateral spinal dorsal horn was transiently increased after LTP induced by HFS, starting at 15 min and returning to control level at 60 min after HFS. Double-labeled immunofluorescence staining demonstrated that p-SFKs were highly restricted to microglia. Furthermore, we found that the inhibitory effects of minocycline or SU6656 on spinal LTP were reversed by spinal application of rat recombinant tumor necrosis factor-alpha (TNF-alpha 0.5 ng/ml, 200 microl). HFS failed to induce LTP of C-fiber evoked field potentials in TNF receptor-1 knockout mice and in rats pretreated with TNF-alpha neutralization antibody (0.6 microg/ml, 200 microl). The results suggested that in spinal dorsal horn activation of SFKs in microglia might control the direction of plastic changes at C-fiber synapses and TNF-alpha might be involved in the process.
authors.affiliation: Pain Research Center, Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Zhou
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Ren
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Xin
authors.forename: Yong-Yong
authors.initials: YY
authors.lastname: Li
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: Xian-Guo
authors.initials: XG
authors.lastname: Liu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015153:Blotting, Western; D004594:Electrophysiology; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology* / Q000502:physiology*; D008911:Minocycline / Q000494:pharmacology; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D020671:Posterior Horn Cells / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D013569:Synapses / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D047428:Protein Kinase Inhibitors; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019061:src-Family Kinases; D008911:Minocycline