基底选择性COX-2抑制IMMA通过内源性大麻素调节和神经炎症抑制减轻创伤后头痛。

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Jie Wen, Mikiei Tanaka, Yumin Zhang
{"title":"基底选择性COX-2抑制IMMA通过内源性大麻素调节和神经炎症抑制减轻创伤后头痛。","authors":"Jie Wen, Mikiei Tanaka, Yumin Zhang","doi":"10.1186/s10194-025-02116-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Posttraumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), characterized by neuroinflammation and pain hypersensitivity. Current treatments are limited, and novel therapeutics are needed. Indomethacin morpholinamide (IMMA), a substrate-selective cyclooxygenase-2 (COX-2) inhibitor, enhances endocannabinoid signaling without disrupting prostaglandin homeostasis and may offer a mechanistically distinct approach to managing PTH.</p><p><strong>Methods: </strong>Male C57BL/6J mice were subjected to repetitive mild TBI (rmTBI) using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) and treated with IMMA (10 mg/kg, i.p.) daily for 7 days post-injury. Mechanical allodynia was assessed using von Frey stimulation of the periorbital region. Neuroinflammation was evaluated through immunohistochemistry in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Endocannabinoid and prostaglandin levels were quantified by mass spectrometry and enzyme immunoassay, respectively.</p><p><strong>Results: </strong>IMMA significantly reduced rmTBI-induced periorbital allodynia, microglial and astrocyte activation, and CGRP expression in the TG and TNC. It also preserved meningeal mast cell integrity and elevated cortical anandamide (AEA) levels without altering prostaglandin E₂ (PGE₂) production, supporting a mechanism that enhances cannabinoid signaling while sparing COX-2-mediated prostaglandin synthesis.</p><p><strong>Conclusion: </strong>IMMA effectively attenuates neuroinflammation and pain hypersensitivity in the acute phase of PTH through a distinct mechanism that preserves endocannabinoid tone without suppressing physiological prostaglandins. While these results highlight its promise as a novel therapeutic strategy, further studies are warranted to determine its efficacy during the chronic phase of PTH and across anatomically targeted regions.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"183"},"PeriodicalIF":7.9000,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341237/pdf/","citationCount":"0","resultStr":"{\"title\":\"Substrate-selective COX-2 inhibition by IMMA attenuates posttraumatic headache via endocannabinoid modulation and neuroinflammatory suppression.\",\"authors\":\"Jie Wen, Mikiei Tanaka, Yumin Zhang\",\"doi\":\"10.1186/s10194-025-02116-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Posttraumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), characterized by neuroinflammation and pain hypersensitivity. Current treatments are limited, and novel therapeutics are needed. Indomethacin morpholinamide (IMMA), a substrate-selective cyclooxygenase-2 (COX-2) inhibitor, enhances endocannabinoid signaling without disrupting prostaglandin homeostasis and may offer a mechanistically distinct approach to managing PTH.</p><p><strong>Methods: </strong>Male C57BL/6J mice were subjected to repetitive mild TBI (rmTBI) using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) and treated with IMMA (10 mg/kg, i.p.) daily for 7 days post-injury. Mechanical allodynia was assessed using von Frey stimulation of the periorbital region. Neuroinflammation was evaluated through immunohistochemistry in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Endocannabinoid and prostaglandin levels were quantified by mass spectrometry and enzyme immunoassay, respectively.</p><p><strong>Results: </strong>IMMA significantly reduced rmTBI-induced periorbital allodynia, microglial and astrocyte activation, and CGRP expression in the TG and TNC. It also preserved meningeal mast cell integrity and elevated cortical anandamide (AEA) levels without altering prostaglandin E₂ (PGE₂) production, supporting a mechanism that enhances cannabinoid signaling while sparing COX-2-mediated prostaglandin synthesis.</p><p><strong>Conclusion: </strong>IMMA effectively attenuates neuroinflammation and pain hypersensitivity in the acute phase of PTH through a distinct mechanism that preserves endocannabinoid tone without suppressing physiological prostaglandins. While these results highlight its promise as a novel therapeutic strategy, further studies are warranted to determine its efficacy during the chronic phase of PTH and across anatomically targeted regions.</p>\",\"PeriodicalId\":16013,\"journal\":{\"name\":\"Journal of Headache and Pain\",\"volume\":\"26 1\",\"pages\":\"183\"},\"PeriodicalIF\":7.9000,\"publicationDate\":\"2025-08-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341237/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Headache and Pain\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s10194-025-02116-x\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Headache and Pain","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s10194-025-02116-x","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景:创伤后头痛(PTH)是创伤性脑损伤(TBI)的一种常见和使人衰弱的后果,以神经炎症和疼痛超敏反应为特征。目前的治疗方法是有限的,需要新的治疗方法。吲哚美辛morpholinamide (IMMA)是一种底物选择性环氧化酶-2 (COX-2)抑制剂,可增强内源性大麻素信号而不破坏前列腺素稳态,可能提供一种机制独特的治疗甲状旁腺激素的方法。方法:采用工程旋转加速度闭头撞击模型(CHIMERA)对雄性C57BL/6J小鼠进行重复性轻度脑损伤(rmTBI),并在损伤后7 d内给予IMMA (10 mg/kg, i.p)治疗。采用von Frey眶周刺激评估机械异常性痛。通过免疫组化评价三叉神经节(TG)和三叉尾核(TNC)的神经炎症。内源性大麻素和前列腺素分别用质谱法和酶免疫分析法测定。结果:IMMA显著降低rmtbi诱导的眶周异常性疼痛、小胶质细胞和星形胶质细胞活化以及TG和TNC中CGRP的表达。它还能保持脑膜肥大细胞的完整性,提高皮质anandamide (AEA)水平,而不改变前列腺素e2 (pge2)的产生,支持一种增强大麻素信号传导的机制,同时保留cox -2介导的前列腺素合成。结论:IMMA通过保留内源性大麻素张力而不抑制生理性前列腺素的独特机制,有效减轻PTH急性期的神经炎症和疼痛超敏反应。虽然这些结果突出了其作为一种新的治疗策略的前景,但需要进一步的研究来确定其在甲状旁腺激素慢性期和解剖靶区域的疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Substrate-selective COX-2 inhibition by IMMA attenuates posttraumatic headache via endocannabinoid modulation and neuroinflammatory suppression.

Background: Posttraumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), characterized by neuroinflammation and pain hypersensitivity. Current treatments are limited, and novel therapeutics are needed. Indomethacin morpholinamide (IMMA), a substrate-selective cyclooxygenase-2 (COX-2) inhibitor, enhances endocannabinoid signaling without disrupting prostaglandin homeostasis and may offer a mechanistically distinct approach to managing PTH.

Methods: Male C57BL/6J mice were subjected to repetitive mild TBI (rmTBI) using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) and treated with IMMA (10 mg/kg, i.p.) daily for 7 days post-injury. Mechanical allodynia was assessed using von Frey stimulation of the periorbital region. Neuroinflammation was evaluated through immunohistochemistry in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Endocannabinoid and prostaglandin levels were quantified by mass spectrometry and enzyme immunoassay, respectively.

Results: IMMA significantly reduced rmTBI-induced periorbital allodynia, microglial and astrocyte activation, and CGRP expression in the TG and TNC. It also preserved meningeal mast cell integrity and elevated cortical anandamide (AEA) levels without altering prostaglandin E₂ (PGE₂) production, supporting a mechanism that enhances cannabinoid signaling while sparing COX-2-mediated prostaglandin synthesis.

Conclusion: IMMA effectively attenuates neuroinflammation and pain hypersensitivity in the acute phase of PTH through a distinct mechanism that preserves endocannabinoid tone without suppressing physiological prostaglandins. While these results highlight its promise as a novel therapeutic strategy, further studies are warranted to determine its efficacy during the chronic phase of PTH and across anatomically targeted regions.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Headache and Pain
Journal of Headache and Pain 医学-临床神经学
CiteScore
11.80
自引率
13.50%
发文量
143
审稿时长
6-12 weeks
期刊介绍: The Journal of Headache and Pain, a peer-reviewed open-access journal published under the BMC brand, a part of Springer Nature, is dedicated to researchers engaged in all facets of headache and related pain syndromes. It encompasses epidemiology, public health, basic science, translational medicine, clinical trials, and real-world data. With a multidisciplinary approach, The Journal of Headache and Pain addresses headache medicine and related pain syndromes across all medical disciplines. It particularly encourages submissions in clinical, translational, and basic science fields, focusing on pain management, genetics, neurology, and internal medicine. The journal publishes research articles, reviews, letters to the Editor, as well as consensus articles and guidelines, aimed at promoting best practices in managing patients with headaches and related pain.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信