生理学报 Acta Physiologica Sinica, October25,2017,695):677-684 677 Dol:10.13294/j.aps.2017.0057http://www.actaps.com.cn 综述 TRPV1:一种同时參与慢性痛外周敏化和疼痛中枢调制的重 要分子 张瑛,王韵2 北京大学医学部基础医学院神经科学研究所,神经生物学系,教育部和卫生与计划生育委员会神经科学重点实验室,北京 100083:2北京大学麦戈文脑科学研究所,北京100871 摘要:慢性痛是困扰临床的一大顽疾,关于慢性痛机制的研究和新型镇痛药物的研发具有重要意义。十多年来,本研究组 目绕慢性痛外周敏化形成的关键分子—瞬时受体电位香草酸亚型1( transient receptor potential vanilloid type I,TRPv1),对 其敏化和膜定位机制进行了系列研究,揭示了蛋白激酶PKDl( protein kinase D1)、Cdk5( cyclin-dependent kinase5)和LIMK (LIM- motif containing kinase)在炎症诱发热痛敏中的作用及其对 TRPVI的功能调控,并据此开发出了一系列具有镇痛作用的 Iat穿膜肽。本综述还围绕研究组近期工作所揭示的参与痛感觉和痛情绪相互作用的关键脑区—一前额叶皮质的前边缘皮质 亚区,对 TRPVI在其中的可能作用进行了探讨。此外本综述也对研究组在改进TRPV1靶向药物,提高其镇痛疗效,降低副 作用方面的工作进行了简要总结和回顾 关词:疼痛:TRPV1:磷酸化:Tat穿膜肽:镇痛 中图分类号:R383:Q432 TRPVI: an important molecule involved in the peripheral sensitization during chronic pain and central pain modulation ZHANG Y WANG Yun.2,. Neuroscience Research institute and Department of Neurobiology. School of Basic Medical Sciences, Key Laboratory for Neuroscience Ministry of Education/National Health and Family Planning Commission, Peking University Health Science Center, Beijing 100083, China; PKU-IDG/McGovern Institute for Brain Research, Peking University Beijing 100871, China Abstract: As chronic pain is a severe problem in clinics, study of the mechanisms of chronic pain and development of novel analgesic agents is of significance. In the past decade, our lab completed a series of studies on the regulatory mechanisms of functional sensiti- zation and membrane trafficking of transient receptor potential vanilloid type 1(TRPVI), a key molecule involved in the development of peripheral sensitization. Our studies elucidated the important regulatory roles of several protein kinases, including PKDl(protein kinase D1), Cdks(cyclin-dependent kinase 5)and LIMK (LIM-motif containing kinase), in inflammatory thermal hyperalgesia. Moreover based on these findings, we constructed a series of transmembrane Tat-fusion peptides for pain relief. The potential role of central TRPVI was discussed as well. Prelimbic subregion of prefrontal cortex was revealed to be a critical brain region involved in the interaction between pain sensation and pain emotions by our recent studies. In addition, our work attempted to improve the analgesic effects of the agents targeting TRPVI and concurrently reduce their side effects. Herein we summarized the work of our lab in pain nd pain modulation during the past decade. Key words: pain; TRPVI; phosphorylation; Tat-transmembrane peptide; analgesia Received 2017-05-17 Accepted 2017-07-20 Research from the corresponding authors laboratory was supported by grants from the National Natural Science Foundation of China(No 3153002, 30925015, 30830044, 31771295, and 31371143) and the National Basic Research Development Program of China(No. 2014CB542204) Corresponding author. Tel: +86-10-82801119: E-mail: wangy66@bjmu edu.生理学报 Acta Physiologica Sinica, October 25, 2017, 69(5): 677–684 DOI: 10.13294/j.aps.2017.0057 http://www.actaps.com.cn 677 TRPV1：一种同时参与慢性痛外周敏化和疼痛中枢调制的重 要分子 张 瑛1 ，王 韵1,2,* 1 北京大学医学部基础医学院神经科学研究所，神经生物学系，教育部和卫生与计划生育委员会神经科学重点实验室，北京 100083；2 北京大学麦戈文脑科学研究所，北京 100871 摘 要：慢性痛是困扰临床的一大顽疾，关于慢性痛机制的研究和新型镇痛药物的研发具有重要意义。十多年来，本研究组 围绕慢性痛外周敏化形成的关键分子——瞬时受体电位香草酸亚型1 (transient receptor potential vanilloid type 1, TRPV1)，对 其敏化和膜定位机制进行了系列研究，揭示了蛋白激酶PKD1 (protein kinase D1)、Cdk5 (cyclin-dependent kinase 5)和LIMK (LIM-motif containing kinase)在炎症诱发热痛敏中的作用及其对TRPV1的功能调控，并据此开发出了一系列具有镇痛作用的 Tat穿膜肽。本综述还围绕研究组近期工作所揭示的参与痛感觉和痛情绪相互作用的关键脑区——前额叶皮质的前边缘皮质 亚区，对TRPV1在其中的可能作用进行了探讨。此外本综述也对研究组在改进TRPV1靶向药物，提高其镇痛疗效，降低副 作用方面的工作进行了简要总结和回顾。 关键词：疼痛；TRPV1；磷酸化；Tat穿膜肽；镇痛 中图分类号：R338.3；Q432 TRPV1: an important molecule involved in the peripheral sensitization during chronic pain and central pain modulation ZHANG Ying1 , WANG Yun1,2,* 1 Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University Health Science Center, Beijing 100083, China; 2 PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China Abstract: As chronic pain is a severe problem in clinics, study of the mechanisms of chronic pain and development of novel analgesic agents is of significance. In the past decade, our lab completed a series of studies on the regulatory mechanisms of functional sensiti￾zation and membrane trafficking of transient receptor potential vanilloid type 1 (TRPV1), a key molecule involved in the development of peripheral sensitization. Our studies elucidated the important regulatory roles of several protein kinases, including PKD1 (protein kinase D1), Cdk5 (cyclin-dependent kinase 5) and LIMK (LIM-motif containing kinase), in inflammatory thermal hyperalgesia. Moreover, based on these findings, we constructed a series of transmembrane Tat-fusion peptides for pain relief. The potential role of central TRPV1 was discussed as well. Prelimbic subregion of prefrontal cortex was revealed to be a critical brain region involved in the interaction between pain sensation and pain emotions by our recent studies. In addition, our work attempted to improve the analgesic effects of the agents targeting TRPV1 and concurrently reduce their side effects. Herein we summarized the work of our lab in pain and pain modulation during the past decade. Key words: pain; TRPV1; phosphorylation; Tat-transmembrane peptide; analgesia Received 2017-05-17 Accepted 2017-07-20 Research from the corresponding author’s laboratory was supported by grants from the National Natural Science Foundation of China (No. 3153002, 30925015, 30830044, 31771295, and 31371143) and the National Basic Research Development Program of China (No. 2014CB542204). * Corresponding author. Tel: +86-10-82801119; E-mail: wangy66@bjmu.edu.cn 综 述