鞘氨醇-1-磷酸受体 1 参与自闭症谱系障碍 BTBR 小鼠模型的疼痛不敏感性研究

IF 7 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL
Lili Fan, Qi Li, Yaxin Shi, Xiang Li, Yutong Liu, Jiaqi Chen, Yaqi Sun, Anjie Chen, Yuan Yang, Xirui Zhang, Jia Wang, Lijie Wu
{"title":"鞘氨醇-1-磷酸受体 1 参与自闭症谱系障碍 BTBR 小鼠模型的疼痛不敏感性研究","authors":"Lili Fan, Qi Li, Yaxin Shi, Xiang Li, Yutong Liu, Jiaqi Chen, Yaqi Sun, Anjie Chen, Yuan Yang, Xirui Zhang, Jia Wang, Lijie Wu","doi":"10.1186/s12916-024-03722-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Abnormal sensory perception, particularly pain insensitivity (PAI), is a typical symptom of autism spectrum disorder (ASD). Despite the role of myelin metabolism in the regulation of pain perception, the mechanisms underlying ASD-related PAI remain unclear.</p><p><strong>Methods: </strong>The pain-associated gene sphingosine-1-phosphate receptor 1 (S1PR1) was identified in ASD samples through bioinformatics analysis. Its expression in the dorsal root ganglion (DRG) tissues of BTBR ASD model mice was validated using RNA-seq, western blot, RT-qPCR, and immunofluorescence. Pain thresholds were assessed using the von Frey and Hargreaves tests. Patch-clamp techniques measured KCNQ/M channel activity and neuronal action potentials. The expression of S1PR1, KCNQ/M, mitogen-activated protein kinase (MAPK), and cyclic AMP/protein kinase A (cAMP/PKA) signaling proteins was analyzed before and after inhibiting the S1P-S1PR1-KCNQ/M pathway via western blot and RT-qPCR.</p><p><strong>Results: </strong>Through integrated transcriptomic analysis of ASD samples, we identified the upregulated gene S1PR1, which is associated with sphingolipid metabolism and linked to pain perception, and confirmed its role in the BTBR mouse model of ASD. This mechanism involves the regulation of KCNQ/M channels in DRG neurons. The enhanced activity of KCNQ/M channels and the decreased action potentials in small and medium DRG neurons were correlated with PAI in a BTBR mouse model of ASD. Inhibition of the S1P/S1PR1 pathway rescued baseline insensitivity to pain by suppressing KCNQ/M channels in DRG neurons, mediated through the MAPK and cAMP/PKA pathways. Investigating the modulation and underlying mechanisms of the non-opioid pathway involving S1PR1 will provide new insights into clinical targeted interventions for PAI in ASD.</p><p><strong>Conclusions: </strong>S1PR1 may contribute to PAI in the PNS in ASD. The mechanism involves KCNQ/M channels and the MAPK and cAMP/PKA signaling pathways. Targeting S1PR1 in the PNS could offer novel therapeutic strategies for the intervention of pain dysesthesias in individuals with ASD.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":7.0000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533282/pdf/","citationCount":"0","resultStr":"{\"title\":\"Involvement of sphingosine-1-phosphate receptor 1 in pain insensitivity in a BTBR mouse model of autism spectrum disorder.\",\"authors\":\"Lili Fan, Qi Li, Yaxin Shi, Xiang Li, Yutong Liu, Jiaqi Chen, Yaqi Sun, Anjie Chen, Yuan Yang, Xirui Zhang, Jia Wang, Lijie Wu\",\"doi\":\"10.1186/s12916-024-03722-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Abnormal sensory perception, particularly pain insensitivity (PAI), is a typical symptom of autism spectrum disorder (ASD). Despite the role of myelin metabolism in the regulation of pain perception, the mechanisms underlying ASD-related PAI remain unclear.</p><p><strong>Methods: </strong>The pain-associated gene sphingosine-1-phosphate receptor 1 (S1PR1) was identified in ASD samples through bioinformatics analysis. Its expression in the dorsal root ganglion (DRG) tissues of BTBR ASD model mice was validated using RNA-seq, western blot, RT-qPCR, and immunofluorescence. Pain thresholds were assessed using the von Frey and Hargreaves tests. Patch-clamp techniques measured KCNQ/M channel activity and neuronal action potentials. The expression of S1PR1, KCNQ/M, mitogen-activated protein kinase (MAPK), and cyclic AMP/protein kinase A (cAMP/PKA) signaling proteins was analyzed before and after inhibiting the S1P-S1PR1-KCNQ/M pathway via western blot and RT-qPCR.</p><p><strong>Results: </strong>Through integrated transcriptomic analysis of ASD samples, we identified the upregulated gene S1PR1, which is associated with sphingolipid metabolism and linked to pain perception, and confirmed its role in the BTBR mouse model of ASD. This mechanism involves the regulation of KCNQ/M channels in DRG neurons. The enhanced activity of KCNQ/M channels and the decreased action potentials in small and medium DRG neurons were correlated with PAI in a BTBR mouse model of ASD. Inhibition of the S1P/S1PR1 pathway rescued baseline insensitivity to pain by suppressing KCNQ/M channels in DRG neurons, mediated through the MAPK and cAMP/PKA pathways. Investigating the modulation and underlying mechanisms of the non-opioid pathway involving S1PR1 will provide new insights into clinical targeted interventions for PAI in ASD.</p><p><strong>Conclusions: </strong>S1PR1 may contribute to PAI in the PNS in ASD. The mechanism involves KCNQ/M channels and the MAPK and cAMP/PKA signaling pathways. Targeting S1PR1 in the PNS could offer novel therapeutic strategies for the intervention of pain dysesthesias in individuals with ASD.</p>\",\"PeriodicalId\":9188,\"journal\":{\"name\":\"BMC Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.0000,\"publicationDate\":\"2024-11-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533282/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"BMC Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12916-024-03722-3\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, GENERAL & INTERNAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"BMC Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12916-024-03722-3","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, GENERAL & INTERNAL","Score":null,"Total":0}
引用次数: 0

摘要

背景:感觉异常,尤其是疼痛不敏感(PAI),是自闭症谱系障碍(ASD)的典型症状。尽管髓鞘代谢在痛觉调节中起着重要作用,但自闭症谱系障碍相关痛觉异常的机制仍不清楚:方法:通过生物信息学分析,在 ASD 样本中发现了疼痛相关基因鞘氨醇-1-磷酸受体 1(S1PR1)。通过RNA-seq、Western印迹、RT-qPCR和免疫荧光等方法验证了S1PR1在BTBR ASD模型小鼠背根神经节(DRG)组织中的表达。使用 von Frey 和 Hargreaves 测试评估了疼痛阈值。膜片钳技术测量了 KCNQ/M 通道活性和神经元动作电位。在抑制 S1P-S1PR1-KCNQ/M 通路前后,通过 Western 印迹和 RT-qPCR 分析了 S1PR1、KCNQ/M、丝裂原活化蛋白激酶(MAPK)和环 AMP/蛋白激酶 A(cAMP/PKA)信号蛋白的表达:结果:通过对ASD样本进行转录组学综合分析,我们发现了与鞘脂代谢相关并与痛觉有关的上调基因S1PR1,并证实了其在BTBR ASD小鼠模型中的作用。这一机制涉及 DRG 神经元中 KCNQ/M 通道的调节。在BTBR ASD小鼠模型中,KCNQ/M通道活性的增强和中小型DRG神经元动作电位的降低与PAI相关。抑制 S1P/S1PR1 通路可通过 MAPK 和 cAMP/PKA 通路抑制 DRG 神经元中的 KCNQ/M 通道,从而挽救对疼痛的基线不敏感性。研究涉及S1PR1的非阿片类通路的调节和潜在机制将为临床靶向干预ASD PAI提供新的见解:结论:S1PR1 可能有助于 ASD 中枢神经系统的 PAI。其机制涉及 KCNQ/M 通道以及 MAPK 和 cAMP/PKA 信号通路。靶向 PNS 中的 S1PR1 可为干预 ASD 患者的痛觉障碍提供新的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Involvement of sphingosine-1-phosphate receptor 1 in pain insensitivity in a BTBR mouse model of autism spectrum disorder.

Background: Abnormal sensory perception, particularly pain insensitivity (PAI), is a typical symptom of autism spectrum disorder (ASD). Despite the role of myelin metabolism in the regulation of pain perception, the mechanisms underlying ASD-related PAI remain unclear.

Methods: The pain-associated gene sphingosine-1-phosphate receptor 1 (S1PR1) was identified in ASD samples through bioinformatics analysis. Its expression in the dorsal root ganglion (DRG) tissues of BTBR ASD model mice was validated using RNA-seq, western blot, RT-qPCR, and immunofluorescence. Pain thresholds were assessed using the von Frey and Hargreaves tests. Patch-clamp techniques measured KCNQ/M channel activity and neuronal action potentials. The expression of S1PR1, KCNQ/M, mitogen-activated protein kinase (MAPK), and cyclic AMP/protein kinase A (cAMP/PKA) signaling proteins was analyzed before and after inhibiting the S1P-S1PR1-KCNQ/M pathway via western blot and RT-qPCR.

Results: Through integrated transcriptomic analysis of ASD samples, we identified the upregulated gene S1PR1, which is associated with sphingolipid metabolism and linked to pain perception, and confirmed its role in the BTBR mouse model of ASD. This mechanism involves the regulation of KCNQ/M channels in DRG neurons. The enhanced activity of KCNQ/M channels and the decreased action potentials in small and medium DRG neurons were correlated with PAI in a BTBR mouse model of ASD. Inhibition of the S1P/S1PR1 pathway rescued baseline insensitivity to pain by suppressing KCNQ/M channels in DRG neurons, mediated through the MAPK and cAMP/PKA pathways. Investigating the modulation and underlying mechanisms of the non-opioid pathway involving S1PR1 will provide new insights into clinical targeted interventions for PAI in ASD.

Conclusions: S1PR1 may contribute to PAI in the PNS in ASD. The mechanism involves KCNQ/M channels and the MAPK and cAMP/PKA signaling pathways. Targeting S1PR1 in the PNS could offer novel therapeutic strategies for the intervention of pain dysesthesias in individuals with ASD.

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
BMC Medicine
BMC Medicine 医学-医学:内科
CiteScore
13.10
自引率
1.10%
发文量
435
审稿时长
4-8 weeks
期刊介绍: BMC Medicine is an open access, transparent peer-reviewed general medical journal. It is the flagship journal of the BMC series and publishes outstanding and influential research in various areas including clinical practice, translational medicine, medical and health advances, public health, global health, policy, and general topics of interest to the biomedical and sociomedical professional communities. In addition to research articles, the journal also publishes stimulating debates, reviews, unique forum articles, and concise tutorials. All articles published in BMC Medicine are included in various databases such as Biological Abstracts, BIOSIS, CAS, Citebase, Current contents, DOAJ, Embase, MEDLINE, PubMed, Science Citation Index Expanded, OAIster, SCImago, Scopus, SOCOLAR, and Zetoc.
×
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