{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:47:08Z","timestamp":1787014028297,"version":"build-2736575974"},"reference-count":57,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171176"],"award-info":[{"award-number":["82171176"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371185"],"award-info":[{"award-number":["82371185"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82401396"],"award-info":[{"award-number":["82401396"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Trigeminal neuropathic pain (TNP) is a debilitating condition characterized by chronic facial pain, yet its underlying mechanisms remain incompletely understood. Transient Receptor Potential Canonical 4 (TRPC4) has been reported to promote the development of abnormal pain or pain hypersensitivity in neuropathic pain. However, the specific contribution of TRPC4 to TNP pathogenesis remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>This study aimed to investigate the role of TRPC4 in a mouse model of trigeminal neuropathic pain induced by chronic constriction of the unilateral infraorbital nerve (CION).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Adult male\/female mice were subjected to either CION surgery or sham surgery. Behavioral assays were conducted to assess facial pain\u2010like responses over a 28\u2010day period. TRPC4 distribution in the trigeminal ganglion (TG) was evaluated using Immunofluorescence. TRPC4 inhibitor ML204 and agonist Englerin A were employed to evaluate the impact of TRPC4 on facial pain\u2010like behaviors. A TRPC4\u2010overexpressing HEK293 cell model was conducted via plasmid transfection. To assess the function of TRPC4, we employed cellular calcium imaging technology to investigate the effects of modulating TRPC4 function by analyzing dynamic changes in intracellular calcium ion concentrations in primary trigeminal ganglion neurons and HEK293 cells.\n                      <jats:italic>Trpc4<\/jats:italic>\n                      shRNA was used to specifically knock down TRPC4 in the trigeminal ganglion. Western blot analysis was used to assess the activation of ERK, P38, and ATF2 signaling pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Mice subjected to CION exhibited persistent facial pain\u2010like behaviors and a significant increase in TRPC4 expression in TG neurons.\n                      <jats:italic>Trpc4<\/jats:italic>\n                      shRNA or pharmacological inhibition with ML204 attenuated CION\u2010induced pain behaviors, while activation of TRPC4 with Englerin A induced pain\u2010like responses in naive mice. Calcium imaging revealed that both Englerin A and TRPC4 overexpression elevated intracellular Ca\u00b2\n                      <jats:sup>2+<\/jats:sup>\n                      levels in TG neurons and HEK293 cells. This Ca\u00b2\n                      <jats:sup>2+<\/jats:sup>\n                      influx triggered the activation of ERK and P38, leading to enhanced ATF2 activation. Downregulation of TRPC4 in the TG reduced ERK\/P38 phosphorylation and ATF2 expression and activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study provides the first evidence that TRPC4 plays a critical role in CION\u2010induced trigeminal neuropathic pain by promoting the activation of the downstream transcription factor ATF2 via the Ca\u00b2\n                      <jats:sup>2+<\/jats:sup>\n                      \u2010ERK\/P38 pathway.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70368","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T06:03:51Z","timestamp":1744178631000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>TRPC4<\/scp>\n                    Mediates Trigeminal Neuropathic Pain via Ca\n                    <sup>2+<\/sup>\n                    \u2010\n                    <scp>ERK<\/scp>\n                    \/\n                    <scp>P38<\/scp>\n                    \u2010\n                    <scp>ATF2<\/scp>\n                    Pathway in the Trigeminal Ganglion of Mice"],"prefix":"10.1111","volume":"31","author":[{"given":"Xinlong","family":"Ke","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajing","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangla","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youfa","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0306-3088","authenticated-orcid":false,"given":"Yongjie","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Hangzhou Normal University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7603-7403","authenticated-orcid":false,"given":"Xiangnan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology &amp; Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China Zhejiang University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeru","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University  Zhejiang Hangzhou China"},{"name":"Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-9491","authenticated-orcid":false,"given":"Gang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University  Zhejiang Hangzhou China"},{"name":"Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aet125"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102416687280"},{"key":"e_1_2_11_4_1","article-title":"Non\u2010Antiepileptic Drugs for Trigeminal Neuralgia","volume":"12","author":"Zhang J.","year":"2013","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.4155\/ppa.15.7"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14578"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.5.2060"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/3764193"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abf5567"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyaa014"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abd7702"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2023.105609"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208886"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2015.09.033"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000154RR"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.765181"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2013.12.043"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2008.12.011"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.117885"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1177\/1744806918787427"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.133625"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2024.01.012"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-020-00621-4"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2023.122283"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(94)90144-9"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww038"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-011-1071-x"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.461"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1203-07.2007"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2025.01.049"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1212\/CON.0000000000001474"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1230633"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2009.08.023"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.2217\/pmt.11.35"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2024.177206"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-016-0652-1"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.250631"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1006-23.2023"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25158204"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14154"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1159\/000112865"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2015.03.017"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/1744\u20108069\u20107\u201081"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000000659"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2006.08.060"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-017-0520-x"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.11607\/ofph.1849"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.npep.2023.102327"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00023.2013"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9020317"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2019.03.005"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000527"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(99)00113-8"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2011.09.060"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2006.09.020"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2009.04.013"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2009.07.001"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24097897"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70368","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cns.70368","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70368","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T15:03:53Z","timestamp":1773068633000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cns.70368"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4]]},"references-count":57,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1111\/cns.70368"],"URL":"https:\/\/doi.org\/10.1111\/cns.70368","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4]]},"assertion":[{"value":"2024-11-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70368"}}