Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases
<p>Abstract</p> <p>Background</p> <p>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). H...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2011-07-01
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| Series: | Molecular Pain |
| Online Access: | http://www.molecularpain.com/content/7/1/50 |
| _version_ | 1811265444230725632 |
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| author | Shimokawa Hiroaki Tozaki-Saitoh Hidetoshi Toyohara Yumiko Tsutsui Masato Tsuda Makoto Kuboyama Kazuya Yanagihara Nobuyuki Inoue Kazuhide |
| author_facet | Shimokawa Hiroaki Tozaki-Saitoh Hidetoshi Toyohara Yumiko Tsutsui Masato Tsuda Makoto Kuboyama Kazuya Yanagihara Nobuyuki Inoue Kazuhide |
| author_sort | Shimokawa Hiroaki |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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 (<it>n/i/eNOS<sup>-/-</sup></it>mice) and investigated the behavioral phenotypes in a series of acute and chronic pain assays.</p> <p>Results</p> <p>In a model of tissue injury-induced pain, evoked by intraplantar injection of formalin, both <it>iNOS<sup>-/-</sup></it>and <it>n/i/eNOS<sup>-/-</sup></it>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 <it>n/i/eNOS<sup>-/-</sup></it>but not <it>iNOS<sup>-/-</sup></it>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.</p> <p>Conclusions</p> <p>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.</p> |
| first_indexed | 2024-04-12T20:24:11Z |
| format | Article |
| id | doaj.art-91fdf4fef95a48cabcd03a4063a6b067 |
| institution | Directory Open Access Journal |
| issn | 1744-8069 |
| language | English |
| last_indexed | 2024-04-12T20:24:11Z |
| publishDate | 2011-07-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Molecular Pain |
| spelling | doaj.art-91fdf4fef95a48cabcd03a4063a6b0672022-12-22T03:17:55ZengSAGE PublishingMolecular Pain1744-80692011-07-01715010.1186/1744-8069-7-50Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthasesShimokawa HiroakiTozaki-Saitoh HidetoshiToyohara YumikoTsutsui MasatoTsuda MakotoKuboyama KazuyaYanagihara NobuyukiInoue Kazuhide<p>Abstract</p> <p>Background</p> <p>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 (<it>n/i/eNOS<sup>-/-</sup></it>mice) and investigated the behavioral phenotypes in a series of acute and chronic pain assays.</p> <p>Results</p> <p>In a model of tissue injury-induced pain, evoked by intraplantar injection of formalin, both <it>iNOS<sup>-/-</sup></it>and <it>n/i/eNOS<sup>-/-</sup></it>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 <it>n/i/eNOS<sup>-/-</sup></it>but not <it>iNOS<sup>-/-</sup></it>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.</p> <p>Conclusions</p> <p>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.</p>http://www.molecularpain.com/content/7/1/50 |
| spellingShingle | Shimokawa Hiroaki Tozaki-Saitoh Hidetoshi Toyohara Yumiko Tsutsui Masato Tsuda Makoto Kuboyama Kazuya Yanagihara Nobuyuki Inoue Kazuhide Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases Molecular Pain |
| title | Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases |
| title_full | Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases |
| title_fullStr | Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases |
| title_full_unstemmed | Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases |
| title_short | Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases |
| title_sort | reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases |
| url | http://www.molecularpain.com/content/7/1/50 |
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