[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-442534-105":59,"doc-detail-442534-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","er-stress-induced-itpr1ano1-signaling-drives-trigeminal-neuropathic-pain-through-calcium-dependent-neuronal-hyperexcitability","ER stress-induced ITPR1/ANO1 signaling drives trigeminal neuropathic pain through calcium-dependent neuronal hyperexcitability","","Endoplasmic reticulum (ER) stress contributes to chronic pain, yet its specific role in trigeminal neuropathic pain (TNP) remains unclear. This study examines how ER stress–induced calcium signaling via the inositol trisphosphate receptor 1 (ITPR1) and anoctamin 1 (ANO1) shapes TNP development in a mouse model. Findings connect ER stress to RUNX2-dependent ITPR1 upregulation and ANO1-coupled neuronal hyperexcitability.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/er-stress-induced-itpr1ano1-signaling-drives-trigeminal-neuropathic-pain-through-calcium-dependent-neuronal-hyperexcitability/442534/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/er-stress-induced-itpr1ano1-signaling-drives-trigeminal-neuropathic-pain-through-calcium-dependent-neuronal-hyperexcitability/442534.png","ImageObject",300,407,{"name":92,"@type":93},"Danger Angel","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main objective of the study?","Question",{"text":112,"@type":113},"To determine how ER stress–induced calcium signaling through ITPR1 and ANO1 contributes to trigeminal neuropathic pain in a mouse model.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was trigeminal neuropathic pain induced and measured?",{"text":117,"@type":113},"A partial infraorbital nerve transection (pIONT) model was used, and mechanical allodynia was assessed with von Frey filaments.",{"name":119,"@type":110,"acceptedAnswer":120},"Which signaling axis is highlighted in the conclusions?",{"text":121,"@type":113},"A RUNX2–ITPR1–ANO1 signaling axis, where ER stress increases RUNX2 and enhances ITPR1 expression, leading to aberrant ER Ca²⁺ release, neuroinflammation, and ANO1-dependent neuronal hyperexcitability.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},442534,1790790970,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":31},962090769052,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","Lu et al. The Journal of Headache and Pain (2026) 27:5  \n[https://doi.org/10.1186/s10194-025-02231-9](https://doi.org/10.1186/s10194-025-02231-9)  \nThe Journal of Headache and Pain  \nRESEARCH Open Access  \nER stress-induced ITPR1/ANO1 signaling  drives trigeminal neuropathic pain through calcium-dependent neuronal hyperexcitability  \nHuan-Jun Lu 1*†, Jia-Wen Shen 1†, Ning-Yi Ren 1, Nan Hu 1, Jian-Ke Cen 1, Meng-Xuan Huang 1, Si-Yuan Song 1, Ling-Jie Ma 1, Xiao-Bo Wu 1, Xia Li 1, Mei-Xian Li 1, Hao Wu 1, Gyu-Sang Hong2, Uhtaek Oh2 and Yong-Jing Gao 1*  \nAbstract  \nBackground Endoplasmic reticulum (ER) stress has been implicated in various chronic pain conditions, but its role in trigeminal neuropathic pain (TNP) remains unclear. This study investigates the contribution of ER stress–induced calcium signaling through the inositol trisphosphate receptor 1 (ITPR1) and anoctamin 1 (ANO1) in a mouse model of TNP.  \nMethods A partial infraorbital nerve transection (pIONT) model was used to induce TNP in mice. Mechanical allodynia was assessed using von Frey filaments. ER stress was evaluated via transmission electron microscopy and Western blotting for ER stress markers. Intracellular Ca²⁺ dynamics were measured by Fluo-4 AM-based Ca²⁺ imaging in primary TG neurons. Gene and protein expression were analyzed using qPCR, Western blot, and immunofluorescence. Protein-protein interaction was examined by co-immunoprecipitation. Neuronal excitability and ANO1 currents were recorded by whole-cell patch-clamp. siRNA-mediated knockdown and pharmacological inhibitors were used to interrogate functional contributions.  \nResults pIONT induced pronounced ER stress inTG neurons, evidenced by swollen ER cisternae and upregulated ER stress sensors. Pharmacological alleviation of ER stress in the TG with the chemical chaperone 4-phenyl butyric acid effectively reduced pIONT-induced pain hypersensitivity. Mechanistically, ER stress upregulated the expression of inositol trisphosphate receptor 1 (ITPR1) via the transcription factor RUNX2, and knockdown of RUNX2 attenuated pIONT-induced mechanical allodynia. Moreover, ITPR1 mediates enhanced ER Ca²⁺ release, ERK activation, and the expression of inflammatory mediators, as well as neuronal hyperexcitability in the TG following pIONT. Notably, ITPR1 functionally couples with anoctamin 1 (ANO1), a calcium-activated chloride channel, inTG neurons. An ITPR1 agonist induced ANO1 currents and mechanical allodynia, which were reduced by an ANO1 inhibitor. Finally, knockdown or inhibition of ANO1 reduced neuronal hypersensitivity and TNP pathogenesis.  \n†Huan-Jun Lu and Jia-Wen Shen contributed equally to this work.  \n*Correspondence:  \nHuan-Jun Lu [huanjunlu@ntu.edu.cn](huanjunlu@ntu.edu.cn)[ ](huanjunlu@ntu.edu.cn)Yong-Jing Gao [gaoyongjing@ntu.edu.cn](gaoyongjing@ntu.edu.cn)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/l](vecommons.org/l)icenses/by-nc-nd/4.0/.  ","cbCaiebdVXxO77JJ","https://ap.wps.com/l/cbCaiebdVXxO77JJ","pdf",4592724,"English","# Abstract\n# Background\n## Trigeminal neuropathic pain and trigeminal ganglion roles\n## ER stress in pain pathogenesis\n# Methods\n# Results\n# Conclusions","[{\"question\":\"What is the main objective of the study?\",\"answer\":\"To determine how ER stress–induced calcium signaling through ITPR1 and ANO1 contributes to trigeminal neuropathic pain in a mouse model.\"},{\"question\":\"How was trigeminal neuropathic pain induced and measured?\",\"answer\":\"A partial infraorbital nerve transection (pIONT) model was used, and mechanical allodynia was assessed with von Frey filaments.\"},{\"question\":\"Which signaling axis is highlighted in the conclusions?\",\"answer\":\"A RUNX2–ITPR1–ANO1 signaling axis, where ER stress increases RUNX2 and enhances ITPR1 expression, leading to aberrant ER Ca²⁺ release, neuroinflammation, and ANO1-dependent neuronal hyperexcitability.\"}]","ER stress-induced ITPR1/ANO1 signaling drives trigeminal neuropathic pain through calcium-dependent neuronal hyperexcitability | PDF",1790700673]