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Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases

Author(s): Kuboyama Kazuya | Tsuda Makoto | Tsutsui Masato | Toyohara Yumiko | Tozaki-Saitoh Hidetoshi | Shimokawa Hiroaki | Yanagihara Nobuyuki | Inoue Kazuhide

Journal: Molecular Pain
ISSN 1744-8069

Volume: 7;
Issue: 1;
Start page: 50;
Date: 2011;
Original page

Abstract Background Several studies have investigated the involvement of nitric oxide (NO) in acute and chronic pain using mice lacking a single NO synthase (NOS) gene among the three isoforms: neuronal (nNOS), inducible (iNOS) and endothelial (eNOS). However, the precise role of NOS/NO in pain states remains to be determined owing to the substantial compensatory interactions among the NOS isoforms. Therefore, in this study, we used mice lacking all three NOS genes (n/i/eNOS-/- mice) and investigated the behavioral phenotypes in a series of acute and chronic pain assays. Results In a model of tissue injury-induced pain, evoked by intraplantar injection of formalin, both iNOS-/- and n/i/eNOS-/- mice exhibited attenuations of pain behaviors in the second phase compared with that in wild-type mice. In a model of neuropathic pain, nerve injury-induced behavioral and cellular responses (tactile allodynia, spinal microglial activation and Src-family kinase phosphorylation) were reduced in n/i/eNOS-/- but not iNOS-/- mice. Tactile allodynia after nerve injury was improved by acute pharmacological inhibition of all NOSs and nNOS. Furthermore, in MG-5 cells (a microglial cell-line), interferon-γ enhanced NOSs and Mac-1 mRNA expression, and the Mac-1 mRNA increase was suppressed by L-NAME co-treatment. Conversely, the NO donor, sodium nitroprusside, markedly increased mRNA expression of Mac-1, interleukin-6, toll-like receptor 4 and P2X4 receptor. Conclusions Our results provide evidence that the NOS/NO pathway contributes to behavioral pain responses evoked by tissue injury and nerve injury. In particular, nNOS may be important for spinal microglial activation and tactile allodynia after nerve injury.

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