通过抑制 CRMP2-Ubc9 相互作用靶向 NaV1.7 的小分子可减少啮齿动物骨关节炎模型中与疼痛相关的结果。

IF 5.9 1区 医学 Q1 ANESTHESIOLOGY
PAIN® Pub Date : 2025-01-01 Epub Date: 2024-07-26 DOI:10.1097/j.pain.0000000000003357
Sara Hestehave, Heather N Allen, Kimberly Gomez, Paz Duran, Aida Calderon-Rivera, Santiago Loya-López, Erick J Rodríguez-Palma, Rajesh Khanna
{"title":"通过抑制 CRMP2-Ubc9 相互作用靶向 NaV1.7 的小分子可减少啮齿动物骨关节炎模型中与疼痛相关的结果。","authors":"Sara Hestehave, Heather N Allen, Kimberly Gomez, Paz Duran, Aida Calderon-Rivera, Santiago Loya-López, Erick J Rodríguez-Palma, Rajesh Khanna","doi":"10.1097/j.pain.0000000000003357","DOIUrl":null,"url":null,"abstract":"<p><strong>Abstract: </strong>Osteoarthritis (OA) is a highly prevalent and disabling joint disease, characterized by pathological progressive joint deformation and clinical symptoms of pain. Disease-modifying treatments remain unavailable, and pain-mitigation is often suboptimal, but recent studies suggest beneficial effects by inhibition of the voltage-gated sodium channel Na V 1.7. We previously identified compound 194 as an indirect inhibitor of Na V 1.7 by preventing SUMOylation of the Na V 1.7-trafficking protein, collapsin response mediator protein 2. Compound 194 reduces the functional activity of Na V 1.7 channels and produces effective analgesia in a variety of acute and neuropathic pain models. However, its effectiveness has not yet been evaluated in models of OA. Here, we explore the effects of 194 on pain-related outcomes in the OA-like monoiodoacetate model using behavioral assessment, biochemistry, novel in vivo fiber photometry, and patch clamp electrophysiology. We found that the monoiodoacetate model induced (1) increased pain-like behaviors and calcium responses of glutamatergic neurons in the parabrachial nucleus after evoked cold and mechanical stimuli, (2) conditioned place aversion to mechanical stimulation, (3) functional weight bearing asymmetry, (4) increased sodium currents in dorsal root ganglia neurons, and (5) increased calcitonin gene-related peptide-release in the spinal cord. Crucially, administration of 194 improved all these pain-related outcomes. Collectively, these findings support indirect inhibition of Na V 1.7 as an effective treatment of OA-related pain through the inhibition of collapsin response mediator protein 2-SUMOylation via compound 194.</p>","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":" ","pages":"99-111"},"PeriodicalIF":5.9000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Small molecule targeting Na V 1.7 via inhibition of CRMP2-Ubc9 interaction reduces pain-related outcomes in a rodent osteoarthritic model.\",\"authors\":\"Sara Hestehave, Heather N Allen, Kimberly Gomez, Paz Duran, Aida Calderon-Rivera, Santiago Loya-López, Erick J Rodríguez-Palma, Rajesh Khanna\",\"doi\":\"10.1097/j.pain.0000000000003357\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Abstract: </strong>Osteoarthritis (OA) is a highly prevalent and disabling joint disease, characterized by pathological progressive joint deformation and clinical symptoms of pain. Disease-modifying treatments remain unavailable, and pain-mitigation is often suboptimal, but recent studies suggest beneficial effects by inhibition of the voltage-gated sodium channel Na V 1.7. We previously identified compound 194 as an indirect inhibitor of Na V 1.7 by preventing SUMOylation of the Na V 1.7-trafficking protein, collapsin response mediator protein 2. Compound 194 reduces the functional activity of Na V 1.7 channels and produces effective analgesia in a variety of acute and neuropathic pain models. However, its effectiveness has not yet been evaluated in models of OA. Here, we explore the effects of 194 on pain-related outcomes in the OA-like monoiodoacetate model using behavioral assessment, biochemistry, novel in vivo fiber photometry, and patch clamp electrophysiology. We found that the monoiodoacetate model induced (1) increased pain-like behaviors and calcium responses of glutamatergic neurons in the parabrachial nucleus after evoked cold and mechanical stimuli, (2) conditioned place aversion to mechanical stimulation, (3) functional weight bearing asymmetry, (4) increased sodium currents in dorsal root ganglia neurons, and (5) increased calcitonin gene-related peptide-release in the spinal cord. Crucially, administration of 194 improved all these pain-related outcomes. Collectively, these findings support indirect inhibition of Na V 1.7 as an effective treatment of OA-related pain through the inhibition of collapsin response mediator protein 2-SUMOylation via compound 194.</p>\",\"PeriodicalId\":19921,\"journal\":{\"name\":\"PAIN®\",\"volume\":\" \",\"pages\":\"99-111\"},\"PeriodicalIF\":5.9000,\"publicationDate\":\"2025-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"PAIN®\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/j.pain.0000000000003357\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"ANESTHESIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"PAIN®","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/j.pain.0000000000003357","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ANESTHESIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

摘要:骨关节炎(OA)是一种发病率高、致残性强的关节疾病,其特点是病理性渐进性关节变形和临床疼痛症状。目前尚无改变疾病的治疗方法,疼痛缓解效果往往不理想,但最近的研究表明,抑制电压门控钠通道 NaV1.7 有益。化合物 194 可降低 NaV1.7 通道的功能活性,并在多种急性和神经病理性疼痛模型中产生有效的镇痛效果。然而,尚未对其在 OA 模型中的有效性进行评估。在这里,我们利用行为评估、生物化学、新型体内纤维光度计和膜片钳电生理学,探讨了 194 对类似 OA 的单碘乙酸盐模型中疼痛相关结果的影响。我们发现,单碘乙酸盐模型会诱发:(1)在诱发冷刺激和机械刺激后,疼痛样行为和胫骨旁核谷氨酸能神经元的钙离子反应增加;(2)对机械刺激的条件性场所厌恶;(3)功能性负重不对称;(4)背根神经节神经元的钠离子电流增加;(5)脊髓降钙素基因相关肽释放增加。最重要的是,服用 194 能改善所有这些与疼痛相关的结果。总之,这些研究结果支持通过化合物 194 抑制塌缩素反应介导蛋白 2-SUMOylation 间接抑制 NaV1.7,从而有效治疗 OA 相关疼痛。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Small molecule targeting Na V 1.7 via inhibition of CRMP2-Ubc9 interaction reduces pain-related outcomes in a rodent osteoarthritic model.

Abstract: Osteoarthritis (OA) is a highly prevalent and disabling joint disease, characterized by pathological progressive joint deformation and clinical symptoms of pain. Disease-modifying treatments remain unavailable, and pain-mitigation is often suboptimal, but recent studies suggest beneficial effects by inhibition of the voltage-gated sodium channel Na V 1.7. We previously identified compound 194 as an indirect inhibitor of Na V 1.7 by preventing SUMOylation of the Na V 1.7-trafficking protein, collapsin response mediator protein 2. Compound 194 reduces the functional activity of Na V 1.7 channels and produces effective analgesia in a variety of acute and neuropathic pain models. However, its effectiveness has not yet been evaluated in models of OA. Here, we explore the effects of 194 on pain-related outcomes in the OA-like monoiodoacetate model using behavioral assessment, biochemistry, novel in vivo fiber photometry, and patch clamp electrophysiology. We found that the monoiodoacetate model induced (1) increased pain-like behaviors and calcium responses of glutamatergic neurons in the parabrachial nucleus after evoked cold and mechanical stimuli, (2) conditioned place aversion to mechanical stimulation, (3) functional weight bearing asymmetry, (4) increased sodium currents in dorsal root ganglia neurons, and (5) increased calcitonin gene-related peptide-release in the spinal cord. Crucially, administration of 194 improved all these pain-related outcomes. Collectively, these findings support indirect inhibition of Na V 1.7 as an effective treatment of OA-related pain through the inhibition of collapsin response mediator protein 2-SUMOylation via compound 194.

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
PAIN®
PAIN® 医学-临床神经学
CiteScore
12.50
自引率
8.10%
发文量
242
审稿时长
9 months
期刊介绍: PAIN® is the official publication of the International Association for the Study of Pain and publishes original research on the nature,mechanisms and treatment of pain.PAIN® provides a forum for the dissemination of research in the basic and clinical sciences of multidisciplinary interest.
×
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:481959085
Book学术官方微信