[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-439399-105":59,"doc-detail-439399-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","morphine-tolerance-gated-through-ezh2-mediated-suppression-of-trpc5-in-spinal-gabaergic-interneurons-in-male-mice","Morphine Tolerance Gated through EZH2-Mediated Suppression of Trpc5 in Spinal GABAergic Interneurons in Male Mice","","A major unresolved issue in severe pain management is opioid-induced tolerance caused by repeated morphine treatment. This study shows that morphine drives persistent downregulation of TRPC5, disrupting Ca2+ homeostasis in spinal dorsal horn GABAergic interneurons and lowering GABA release. Enhancing TRPC5 activity via riluzole or lentiviral overexpression prolongs morphine’s analgesic effect, whereas TRPC5 inhibition or TRPC5 knockout accelerates tolerance. Mechanistically, EZH2-dependent epigenetic repression at the Trpc5 promoter reduces RNA polymerase II enrichment and increases H3K27me3; blocking EZH2 with EPZ6438 or silencing EZH2 restores tolerance.",{"@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/morphine-tolerance-gated-through-ezh2-mediated-suppression-of-trpc5-in-spinal-gabaergic-interneurons-in-male-mice/439399/",{"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/morphine-tolerance-gated-through-ezh2-mediated-suppression-of-trpc5-in-spinal-gabaergic-interneurons-in-male-mice/439399.png","ImageObject",300,407,{"name":92,"@type":93},"Angel","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does morphine tolerance develop according to the study?","Question",{"text":112,"@type":113},"Tolerance involves persistent downregulation of TRPC5 in spinal GABAergic interneurons, which impairs Ca2+ homeostasis and reduces GABA release, weakening morphine analgesia over time.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What happens when TRPC5 is activated or overexpressed in spinal GABAergic interneurons?",{"text":117,"@type":113},"Spinal TRPC5 activation by riluzole or lentiviral-mediated TRPC5 overexpression produces a long-lasting enhancement of morphine’s analgesic effect.",{"name":119,"@type":110,"acceptedAnswer":120},"How is EZH2 involved mechanistically in TRPC5 suppression and morphine tolerance?",{"text":121,"@type":113},"Morphine increases EZH2 binding at the Trpc5 promoter, elevates H3K27me3, and decreases RNA polymerase II enrichment. Pharmacological blockade of EZH2 with EPZ6438 or genetic silencing reverses morphine tolerance.","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},439399,1791161277,{"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":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},687207412472,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","RESEARCH ARTICLE  \n[www.advancedscience.com](www.advancedscience.com)  \nMorphine Tolerance Gated through EZH2-Mediated Suppression ofTrpc5 in Spinal GABAergic Interneurons in Male Mice  \nLi Wan, Mengyao Zhang, Haiyue Guo, Yan Xu, Chenjie Xu, Fan Hu, Yinbing Pan, Xian Wang,* Wentao Liu,* and Chun-Yi Jiang*  \nA major unresolved issue in managing severe pain is tolerance caused by repeated treatment of opioid analgesics. Here, it is demonstrated that tolerance-inducing treatment with morphine results in the persistent downregulation of transient receptor potential canonical 5 (TRPC5), impairing the Ca2+ homeostasis in GABAergic interneurons of the spinal dorsal horn (SDH) and consequently reducing GABA release. Spinal activation ofTRPC5 by riluzole (RLZ) or lentiviral-mediated TRPC5 overexpression in GABAergic interneurons produces a long-lasting enhancement of morphine’s analgesic effect. In contrast, pharmacological inhibition ofTRPC5 and mice lacking TRPC5 accelerates the development of morphine tolerance. Mechanistically, it is found that transcriptional suppression ofTrpc5 results from enhancer of zeste homolog 2 (EZH2)-mediated epigenetic modifications at the Trpc5 gene promoter. Morphine decreases the enrichment of RNA polymerase II at the Trpc5 promoter. Moreover, exposure to morphine increases EZH2 binding to the Trpc5 promoter, leading to the enrichment of histone H3 lysine-27 trimethylation (H3K27me3). Pharmacological blockade of EZH2 by EPZ6438 or genetic silencing in GABAergic interneurons reverses morphine tolerance. Thus, it is proposed that the clinical translation of these findings may help reduce the suffering of individuals with intractable pain.  \n1. Introduction  \nPain is recognized as a global health problem with a profound impact on quality life. Opioids have been essential for pain management, as endorsed by the World Health Organization (WHO) . Since the 1990s, global opioid consumption has increased, with morphine being the second most consumed opioid, primarily for cancer pain relief and palliative care. [1,2] Morphine is widely utilized due to its affordability and strong analgesic effects, but its use is often compromised by the development of tolerance. Despite this, safe and effective therapeutic alternatives remain limited. The spinal dorsal horn (SDH) is the primary site of action for morphine’s analgesic effect. Long-term morphine exposure leads to adaptations in many signaling proteins within SDH, which have been proposed as mechanisms of analgesic tolerance. [3,4] Noxious information from primary afferents is processed by complex circuits in SDH,  \nL. Wan, M. Zhang, H. Guo, F. Hu, W. Liu, C.-Y. Jiang Jiangsu Key Laboratory of Neurodegeneration  \nDepartment of Pharmacology Nanjing Medical University Nanjing, Jiangsu 211166, China  \nE-mail: [painresearch@njmu.edu.cn](painresearch@njmu.edu.cn); [jcy@njmu.edu.cn](jcy@njmu.edu.cn)  \nL. Wan  \nState Key Laboratory of Pharmaceutical Biotechnology School of Life Sciences  \nNanjing University  \nNanjing, Jiangsu 210023, China  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202507908](https://doi.org/10.1002/advs.202507908)[ ](https://doi.org/10.1002/advs.202507908)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nDOI: 10.1002/advs.202507908  \nY. Xu  \nDepartment of Pain  \nthe first people ‘s hospital ofChangzhou Soochow University  \nChangzhou, Jiangsu 213000, China  \nC. Xu  \nDepartment of Anesthesiology and Pain Nanjing First Hospital  \nNanjing Medical University Nanjing, Jiangsu 210006, China  \nY. Pan  \nDepartment of Anesthesiology  \nThe First Affiliated Hospital of Nanjing Medical University Nanjing, Jiangsu 210029, China  \nX. Wang  \nDepartment of Anesthesiology, Women’s Hospi","cbCaigxVUXzKQJPW","https://ap.wps.com/l/cbCaigxVUXzKQJPW","pdf",5497134,25,"English","# Introduction\n## Opioid tolerance and morphine usage\n## Spinal dorsal horn and excitatory-inhibitory balance\n## Descending pain modulation pathways\n## Role of spinal GABAergic interneurons\n## Clinical relevance of intrathecal morphine","[{\"question\":\"How does morphine tolerance develop according to the study?\",\"answer\":\"Tolerance involves persistent downregulation of TRPC5 in spinal GABAergic interneurons, which impairs Ca2+ homeostasis and reduces GABA release, weakening morphine analgesia over time.\"},{\"question\":\"What happens when TRPC5 is activated or overexpressed in spinal GABAergic interneurons?\",\"answer\":\"Spinal TRPC5 activation by riluzole or lentiviral-mediated TRPC5 overexpression produces a long-lasting enhancement of morphine’s analgesic effect.\"},{\"question\":\"How is EZH2 involved mechanistically in TRPC5 suppression and morphine tolerance?\",\"answer\":\"Morphine increases EZH2 binding at the Trpc5 promoter, elevates H3K27me3, and decreases RNA polymerase II enrichment. Pharmacological blockade of EZH2 with EPZ6438 or genetic silencing reverses morphine tolerance.\"}]","Morphine Tolerance Gated through EZH2-Mediated Suppression of Trpc5 in Spinal GABAergic Interneurons in Male Mice | PDF",1790688473,63]