{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T17:46:22Z","timestamp":1772559982443,"version":"3.50.1"},"reference-count":31,"publisher":"Georg Thieme Verlag KG","issue":"02","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":36,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Neurol Surg Rep"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic pancreatitis (CP) is marked by persistent inflammation and fibrosis of the pancreas, often causing severe abdominal pain. The pain mechanism involves complex interactions between pancreatic inflammation and spinal nerve activity. Histone deacetylase 2 (HDAC2) is implicated in neural processes and pain modulation, making it a potential target for CP pain management.<\/jats:p><jats:p>This study investigates HDAC2's role in CP pain and evaluates the effects of its inhibition in a CP rat model.<\/jats:p><jats:p>CP was induced in male Sprague\u2013Dawley rats using dibutyltin dichloride (DBTC). HDAC2 expression in spinal and pancreatic tissues was assessed through western blotting, quantitative Real-Time PCR, and enzyme-linked immunosorbent assay (ELISA). Pain sensitivity was evaluated using paw withdrawal tests. Co-cultures of AR42J pancreatic acinar cells and F11 spinal neurons were used to explore pancreatic\u2013neural interactions. Chromatin immunoprecipitation (ChIP) and promoter assays examined HDAC2 transcriptional regulation.<\/jats:p><jats:p>HDAC2 expression was significantly elevated in CP rats, which also displayed increased pain sensitivity and higher inflammatory markers (interleukin [IL]-1\u03b2 [IL-1\u03b2], tumor necrosis factor-\u03b1 [TNF-\u03b1], IL-6, and chemokine ligand 2 [CCL-2]). HDAC2 inhibition reduced pain sensitivity and pancreatitis. Co-culture experiments revealed that pancreatic inflammatory mediators upregulate HDAC2 in neurons. ChIP identified Sp1 as a regulatory factor for HDAC2, with the extracellular signal-regulated kinase-Specific protein 1 (ERK-Sp1) pathway critical for its expression.<\/jats:p><jats:p>HDAC2 is crucial in CP pain sensitization and inflammation. Its inhibition reduces pain and inflammation, offering potential for targeted pain management in CP.<\/jats:p>","DOI":"10.1055\/a-2561-8065","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T23:09:14Z","timestamp":1746659354000},"page":"e99-e106","source":"Crossref","is-referenced-by-count":1,"title":["The Mechanism of HDAC2 Inhibitors on Chronic Pancreatitis Pain"],"prefix":"10.1055","volume":"86","author":[{"given":"Xiang-tian","family":"Zeng","sequence":"additional","affiliation":[{"name":"Central Supply Service Department, Ganzhou People's Hospital, Ganzhou, Jiangxi, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital, Ganzhou, Jiangxi, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ding-wen","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital, Ganzhou, Jiangxi, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi-xin","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital, Ganzhou, Jiangxi, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"He","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital, Ganzhou, Jiangxi, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong-Qiang","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital, Ganzhou, Jiangxi, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiu-lin","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital, Ganzhou, Jiangxi, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1847-5146","authenticated-orcid":false,"given":"Yong-hui","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital, Ganzhou, Jiangxi, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"17060","DOI":"10.1038\/nrdp.2017.60","article-title":"Chronic pancreatitis","volume":"3","author":"J Kleeff","year":"2017","journal-title":"Nat Rev Dis Primers"},{"issue":"02","key":"ref2","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S1542-3565(05)00981-X","article-title":"Health-related quality of life in patients attending a gastroenterology outpatient clinic: functional disorders versus organic diseases","volume":"4","author":"M Simr\u00e9n","year":"2006","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"11","key":"ref3","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1136\/gut.2007.146621","article-title":"Pain in chronic pancreatitis: the role of neuropathic pain mechanisms","volume":"57","author":"A M Drewes","year":"2008","journal-title":"Gut"},{"issue":"03","key":"ref4","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/nrgastro.2011.274","article-title":"Unraveling the mystery of pain in chronic pancreatitis","volume":"9","author":"P J Pasricha","year":"2012","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"01","key":"ref5","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.pan.2015.10.015","article-title":"Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group","volume":"16","author":"M A Anderson","year":"2016","journal-title":"Pancreatology"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.pain.2005.06.013","article-title":"Molecular and behavioral changes in nociception in a novel rat model of chronic pancreatitis for the study of pain","volume":"117","author":"J H Winston","year":"2005","journal-title":"Pain"},{"issue":"01","key":"ref7","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1053\/j.gastro.2011.09.041","article-title":"Spinal microglia initiate and maintain hyperalgesia in a rat model of chronic pancreatitis","volume":"142","author":"P Y Liu","year":"2012","journal-title":"Gastroenterology"},{"issue":"06","key":"ref8","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.jcmgh.2015.07.008","article-title":"P2\u2009\u00d7\u20097 receptor mediates spinal microglia activation of visceral hyperalgesia in a rat model of chronic pancreatitis","volume":"1","author":"P Y Liu","year":"2015","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"02","key":"ref9","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s12276-020-0382-4","article-title":"A short guide to histone deacetylases including recent progress on class II enzymes","volume":"52","author":"S Y Park","year":"2020","journal-title":"Exp Mol Med"},{"issue":"12","key":"ref10","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.tips.2009.09.007","article-title":"HDAC2: a critical factor in health and disease","volume":"30","author":"O H Kr\u00e4mer","year":"2009","journal-title":"Trends Pharmacol Sci"},{"issue":"7243","key":"ref11","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nature07925","article-title":"HDAC2 negatively regulates memory formation and synaptic plasticity","volume":"459","author":"J S Guan","year":"2009","journal-title":"Nature"},{"issue":"355","key":"ref12","doi-asserted-by":"crossref","first-page":"re12","DOI":"10.1126\/scisignal.aaa0069","article-title":"Histone deacetylases in memory and cognition","volume":"7","author":"J Penney","year":"2014","journal-title":"Sci Signal"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"346","DOI":"10.3389\/fnins.2019.00346","article-title":"Normalizing HDAC2 levels in the spinal cord alleviates thermal and mechanical hyperalgesia after peripheral nerve injury and promotes GAD65 and KCC2 expression","volume":"13","author":"B Ouyang","year":"2019","journal-title":"Front Neurosci"},{"issue":"48","key":"ref14","doi-asserted-by":"crossref","first-page":"8918","DOI":"10.1523\/JNEUROSCI.0735-22.2022","article-title":"HDAC2 in primary sensory neurons constitutively restrains chronic pain by repressing \u03b12\u03b4-1 expression and associated NMDA receptor activity","volume":"42","author":"J Zhang","year":"2022","journal-title":"J Neurosci"},{"issue":"04","key":"ref15","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1007\/s13577-020-00387-x","article-title":"HDAC inhibitors promote pancreatic stellate cell apoptosis and relieve pancreatic fibrosis by upregulating miR-15\/16 in chronic pancreatitis","volume":"33","author":"T Ji","year":"2020","journal-title":"Hum Cell"},{"issue":"02","key":"ref16","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/ijc.30438","article-title":"Normalizing GDNF expression in the spinal cord alleviates cutaneous hyperalgesia but not ongoing pain in a rat model of bone cancer pain","volume":"140","author":"Z Ding","year":"2017","journal-title":"Int J Cancer"},{"issue":"23","key":"ref17","doi-asserted-by":"crossref","first-page":"7165","DOI":"10.1158\/1078-0432.CCR-06-1393","article-title":"A novel anticancer effect of thalidomide: inhibition of intercellular adhesion molecule-1-mediated cell invasion and metastasis through suppression of nuclear factor-kappaB","volume":"12","author":"Y C Lin","year":"2006","journal-title":"Clin Cancer Res"},{"issue":"05","key":"ref18","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1002\/ca.23882","article-title":"The deep fascia and its role in chronic pain and pathological conditions: A review","volume":"35","author":"F Kondrup","year":"2022","journal-title":"Clin Anat"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1159\/000108958","article-title":"Pain in chronic pancreatitis: a salutogenic mechanism or a maladaptive brain response?","volume":"7","author":"F Fregni","year":"2007","journal-title":"Pancreatology"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"174202","DOI":"10.1016\/j.scitotenv.2024.174202","article-title":"Exposure to coal dust exacerbates cognitive impairment by activating the IL6\/ERK1\/2\/SP1 signaling pathway","volume":"946","author":"F Cai","year":"2024","journal-title":"Sci Total Environ"},{"issue":"10","key":"ref21","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/s41580-020-0255-7","article-title":"ERK signalling: a master regulator of cell behaviour, life and fate","volume":"21","author":"H Lavoie","year":"2020","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"04","key":"ref22","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1096\/fj.06-7859rev","article-title":"Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival","volume":"22","author":"M R Junttila","year":"2008","journal-title":"FASEB J"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.lfs.2008.06.024","article-title":"A critical role of Sp1 transcription factor in regulating gene expression in response to insulin and other hormones","volume":"83","author":"S S Solomon","year":"2008","journal-title":"Life Sci"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0303-7207(02)00221-6","article-title":"Regulation of the activity of Sp1-related transcription factors","volume":"195","author":"P Bouwman","year":"2002","journal-title":"Mol Cell Endocrinol"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"105090","DOI":"10.1016\/j.phrs.2020.105090","article-title":"Map kinase signaling as therapeutic target for neurodegeneration","volume":"160","author":"T Ahmed","year":"2020","journal-title":"Pharmacol Res"},{"issue":"06","key":"ref26","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/mp.2014.136","article-title":"Neurotrophic factor-\u03b11 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone","volume":"20","author":"Y Cheng","year":"2015","journal-title":"Mol Psychiatry"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"114659","DOI":"10.1016\/j.expneurol.2023.114659","article-title":"Ferrostatin-1 improves neurological impairment induced by ischemia\/reperfusion injury in the spinal cord through ERK1\/2\/SP1\/GPX4","volume":"373","author":"S Liu","year":"2024","journal-title":"Exp Neurol"},{"issue":"10","key":"ref28","doi-asserted-by":"crossref","first-page":"5342","DOI":"10.4049\/jimmunol.168.10.5342","article-title":"p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease","volume":"168","author":"G H Waetzig","year":"2002","journal-title":"J Immunol"},{"issue":"07","key":"ref29","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/aps.2012.36","article-title":"The mineralocorticoid receptor-p38MAPK-NF\u03baB or ERK-Sp1 signal pathways mediate aldosterone-stimulated inflammatory and profibrotic responses in rat vascular smooth muscle cells","volume":"33","author":"C J Zhu","year":"2012","journal-title":"Acta Pharmacol Sin"},{"issue":"12","key":"ref30","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1002\/ptr.5686","article-title":"Silibinin inhibits neutrophilic inflammation and mucus secretion induced by cigarette smoke via suppression of ERK-SP1 pathway","volume":"30","author":"J W Park","year":"2016","journal-title":"Phytother Res"},{"issue":"01","key":"ref31","doi-asserted-by":"crossref","first-page":"14690","DOI":"10.1038\/s41598-018-32927-9","article-title":"Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo","volume":"8","author":"R DW Kelly","year":"2018","journal-title":"Sci Rep"}],"container-title":["Journal of Neurological Surgery Reports"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2561-8065.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T23:09:19Z","timestamp":1746659359000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2561-8065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4]]},"references-count":31,"journal-issue":{"issue":"02","published-online":{"date-parts":[[2025,4,3]]},"published-print":{"date-parts":[[2025,4]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2561-8065","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["2193-6358","2193-6366"],"issn-type":[{"value":"2193-6358","type":"print"},{"value":"2193-6366","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4]]}}}