{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:42:06Z","timestamp":1792521726303,"version":"4.5.0"},"reference-count":63,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2010,1,1]],"date-time":"2010-01-01T00:00:00Z","timestamp":1262304000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Mol Pain"],"published-print":{"date-parts":[[2010,1,1]]},"abstract":"<jats:sec><jats:title>Background:<\/jats:title><jats:p> Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p> Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-10), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1\u03b2. The increase of the antiinflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-10, and IL-10 following CFA, overall corroborating the inhibitor data. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion:<\/jats:title><jats:p> These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression. <\/jats:p><\/jats:sec>","DOI":"10.1186\/1744-8069-6-13","type":"journal-article","created":{"date-parts":[[2010,3,2]],"date-time":"2010-03-02T07:16:23Z","timestamp":1267514183000},"source":"Crossref","is-referenced-by-count":66,"title":["Nitric Oxide Synthase Modulates CFA-Induced Thermal Hyperalgesia through Cytokine Regulation in Mice"],"prefix":"10.1177","volume":"6","author":[{"given":"Yong","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurology, University of W\u00fcrzburg, Josef-Schneider-Str 11, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael 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