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However, the molecular mechanisms underlying intraoral pain remain unclear. Here, we investigated gene modulation in the trigeminal ganglion and intraoral pain-related behavior in a rat model of acetic acid-induced oral ulcerative mucositis. Oral ulceration was observed on day 2 after acetic acid treatment to the oral mucosa of male Wistar rats, causing spontaneous pain and mechanical allodynia. Deoxyribonucleic acid microarray analysis of trigeminal ganglion tissue indicated that <jats:italic>Hamp<\/jats:italic> (a hepcidin gene that regulates cellular iron transport) was the most upregulated gene. In the oral ulcerative mucositis model, the upregulation of <jats:italic>Hamp<\/jats:italic> was also induced in the ulcer region but not in the liver, with no increase in hepcidin levels in the plasma and saliva, indicating that hepcidin was produced locally in the ulcer region in the model. Systemic antibiotic pretreatment did not increase the mRNA levels of <jats:italic>Hamp<\/jats:italic> in the trigeminal ganglion and ulcer regions. Hepcidin injection into the oral mucosa enhanced neuronal excitability in response to noxious mechanical stimulation of the oral mucosa in trigeminal spinal subnucleus interpolaris\/caudalis neurons. These results imply that oral ulcerative mucositis induces oral mucosal pain because of infectious inflammation of the ulcerative area and potentiates <jats:italic>Hamp<\/jats:italic>, which represents anti-bacterial and anti-peptidase gene expression in the ulcer region and trigeminal ganglion. The regulation of cellular iron transport by hepcidin is likely involved in oral ulcerative mucositis-induced pain.<\/jats:p>","DOI":"10.1371\/journal.pone.0284617","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T18:10:05Z","timestamp":1682014205000},"page":"e0284617","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Hepcidin expression in the trigeminal ganglion and the oral mucosa in an oral ulcerative mucositis rat model"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3311-1519","authenticated-orcid":true,"given":"Suzuro","family":"Hitomi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomotaka","family":"Nodai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoichiro","family":"Kokabu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takemi","family":"Shikayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misa","family":"Sago-Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chihiro","family":"Nakatomi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiyoshi","family":"Terawaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Omiya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masamichi","family":"Shinoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kentaro","family":"Ono","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,4,20]]},"reference":[{"issue":"6306","key":"pone.0284617.ref001","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1136\/bmj.283.6306.1569","article-title":"Role of mucosal injury in initiating recurrent aphthous stomatitis","volume":"283","author":"D Wray","year":"1981","journal-title":"Br Med J (Clin Res Ed)."},{"issue":"3","key":"pone.0284617.ref002","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.1365-2230.2009.03220.x","article-title":"Oral ulcers: clinical aspects. 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Donnelly","year":"2003","journal-title":"Lancet Infect Dis"},{"issue":"3","key":"pone.0284617.ref006","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/S0167-8140(02)00404-8","article-title":"Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review","volume":"66","author":"A Trotti","year":"2003","journal-title":"Radiother Oncol"},{"issue":"6 Suppl 3","key":"pone.0284617.ref007","first-page":"3","article-title":"Oral mucositis in cancer therapy","volume":"2","author":"ST Sonis","year":"2004","journal-title":"J Support Oncol"},{"issue":"4","key":"pone.0284617.ref008","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/0030-4220(90)90376-4","article-title":"An animal model for mucositis induced by cancer chemotherapy","volume":"69","author":"ST Sonis","year":"1990","journal-title":"Oral surgery, oral medicine, and oral 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Yamaguchi","year":"2016","journal-title":"Pain"},{"issue":"8","key":"pone.0284617.ref015","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1177\/0022034518762381","article-title":"Endothelin-1 Elicits TRP-Mediated Pain in an Acid-Induced Oral Ulcer Model","volume":"97","author":"T Nodai","year":"2018","journal-title":"Journal of dental research"},{"issue":"3","key":"pone.0284617.ref016","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/j.1600-0722.2005.00216.x","article-title":"Effects of the tumour necrosis factor-alpha inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters","volume":"113","author":"V Lima","year":"2005","journal-title":"European journal of oral sciences"},{"issue":"8","key":"pone.0284617.ref017","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.pain.2011.04.014","article-title":"Patterns of pain: meta-analysis of microarray studies of pain","volume":"152","author":"ML 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Zimmermann","year":"1983","journal-title":"Pain"},{"key":"pone.0284617.ref020","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.neulet.2017.03.023","article-title":"Enhancement of ERK phosphorylation and photic responses in Vc\/C1 neurons of a migraine model","volume":"647","author":"S Hitomi","year":"2017","journal-title":"Neuroscience letters"},{"issue":"2","key":"pone.0284617.ref021","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.archoralbio.2013.11.001","article-title":"Changes of salivary functions in experimental periodontitis model rats","volume":"59","author":"M Nakamura-Kiyama","year":"2014","journal-title":"Archives of oral biology"},{"key":"pone.0284617.ref022","doi-asserted-by":"crossref","first-page":"104775","DOI":"10.1016\/j.archoralbio.2020.104775","article-title":"Hematogenous apoptotic mechanism in salivary glands in chronic periodontitis","volume":"117","author":"T Shikayama","year":"2020","journal-title":"Archives of oral biology"},{"issue":"36","key":"pone.0284617.ref023","doi-asserted-by":"crossref","first-page":"11161","DOI":"10.1523\/JNEUROSCI.3365-09.2009","article-title":"Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms.","volume":"29","author":"A Okada-Ogawa","year":"2009","journal-title":"J Neurosci"},{"issue":"4","key":"pone.0284617.ref024","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.","volume":"25","author":"KJ Livak","year":"2001","journal-title":"Methods"},{"issue":"5","key":"pone.0284617.ref025","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1152\/jn.00794.2007","article-title":"Modulation of trigeminal spinal subnucleus caudalis neuronal activity following regeneration of transected inferior alveolar nerve in rats","volume":"99","author":"K Saito","year":"2008","journal-title":"J Neurophysiol"},{"key":"pone.0284617.ref026","article-title":"Activation of dura-sensitive trigeminal neurons and increased c-Fos protein induced by morphine withdrawal in the rostral ventromedial medulla","author":"S Hitomi","year":"2016","journal-title":"Cephalalgia: an international journal of headache"},{"issue":"1","key":"pone.0284617.ref027","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"R Edgar","year":"2002","journal-title":"Nucleic acids research"},{"issue":"3","key":"pone.0284617.ref028","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1093\/biostatistics\/kxp003","article-title":"A note on oligonucleotide expression values not being normally distributed.","volume":"10","author":"J Hardin","year":"2009","journal-title":"Biostatistics."},{"issue":"1","key":"pone.0284617.ref029","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"W Huang da","year":"2009","journal-title":"Nucleic acids research"},{"issue":"3","key":"pone.0284617.ref030","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.pain.2006.11.017","article-title":"Role of the cysteine protease cathepsin S in neuropathic hyperalgesia","volume":"130","author":"J Barclay","year":"2007","journal-title":"Pain"},{"issue":"9","key":"pone.0284617.ref031","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1093\/brain\/awq195","article-title":"Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1","volume":"133","author":"M Costigan","year":"2010","journal-title":"Brain: a journal of neurology"},{"issue":"9","key":"pone.0284617.ref032","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1172\/JCI200420945","article-title":"IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin","volume":"113","author":"E Nemeth","year":"2004","journal-title":"The Journal of clinical investigation"},{"key":"pone.0284617.ref033","doi-asserted-by":"crossref","first-page":"740","DOI":"10.3389\/fnins.2018.00740","article-title":"The Dual Role of Hepcidin in Brain Iron Load and Inflammation","volume":"12","author":"D. Vela","year":"2018","journal-title":"Front Neurosci"},{"issue":"6108","key":"pone.0284617.ref034","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1126\/science.1224577","article-title":"Hepcidin and the iron-infection axis","volume":"338","author":"H Drakesmith","year":"2012","journal-title":"Science"},{"issue":"12","key":"pone.0284617.ref035","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22126493","article-title":"Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis.","volume":"22","author":"E Nemeth","year":"2021","journal-title":"Int J Mol Sci."},{"issue":"12","key":"pone.0284617.ref036","doi-asserted-by":"crossref","first-page":"118535","DOI":"10.1016\/j.bbamcr.2019.118535","article-title":"Iron homeostasis and oxidative stress: An intimate relationship","volume":"1866","author":"D Galaris","year":"2019","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"issue":"3","key":"pone.0284617.ref037","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/intimm\/dxaa078","article-title":"IL-6 in inflammation, autoimmunity and cancer","volume":"33","author":"T. Hirano","year":"2021","journal-title":"Int Immunol"},{"issue":"5","key":"pone.0284617.ref038","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/hep4.1717","article-title":"Hepcidin Signaling in Health and Disease: Ironing Out the Details.","volume":"5","author":"KV Kowdley","year":"2021","journal-title":"Hepatol Commun."},{"issue":"28","key":"pone.0284617.ref039","doi-asserted-by":"crossref","first-page":"10357","DOI":"10.1523\/JNEUROSCI.1249-15.2015","article-title":"mRNAs and Protein Synthetic Machinery Localize into Regenerating Spinal Cord Axons When They Are Provided a Substrate That Supports Growth","volume":"35","author":"AL Kalinski","year":"2015","journal-title":"J Neurosci"},{"issue":"10","key":"pone.0284617.ref040","doi-asserted-by":"crossref","first-page":"13615","DOI":"10.18632\/aging.202887","article-title":"The effect of IL-6\/Piezo2 on the trigeminal neuropathic pain","volume":"13","author":"M Liu","year":"2021","journal-title":"Aging (Albany 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