Journal
MOLECULAR PAIN
Volume 7, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/1744-8069-7-50
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Society for the Promotion of Science (JSPS)
- Next Generation World-Leading Researchers (NEXT Program)
- Grants-in-Aid for Scientific Research [23229008, 23617035, 23617036, 23590159, 23590305] Funding Source: KAKEN
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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-gamma 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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