《神经科学杂志》：王韵小组吗啡耐受研究获重要进展

有人说，在系统研究中发表5篇以上高水平文章，
就算得上该领域的牛人。王韵教授似乎就是这样的人。

吗啡是临床上最有效，也是使用最广泛的镇痛剂，但长期使用吗啡会带来诸如耐受和成瘾等副作用，从而大大限制了吗啡在临床上的使用。

北京大学神经科学研究所王韵教授科研组在细胞周期素激酶5（Cdk5）对吗啡耐受产生及调节机制方面进行了系列研究，目前取得重要进展，研究论文将于2009年3月18日在国际神经科学权威杂志《神经科学杂志》（The Journal of Neuroscience）发表。

Cdk5属于细胞周期素激酶家族，但它和该家族其他成员不同，不参与细胞周期调控，却在有丝分裂后细胞如神经元中活性最高，并且在中枢神经系统功能调节中发挥重要作用。王韵科研组研究工作表明，Cdk5通过磷酸化吗啡内源性受体之一delta受体的第二胞内环中161位苏氨酸，影响delta受体膜转运，继而促进吗啡耐受，干扰161位苏氨酸的磷酸化，则会明显延缓吗啡耐受。该研究组成员根据delta受体的第二胞内环设计了一段能自由穿过细胞膜的短肽，该干扰肽进入细胞内能明显干扰161位苏氨酸的磷酸化，在动物实验中，该干扰肽也能够明显延缓吗啡耐受，这一发现使得该研究不仅对于吗啡耐受分子机制的基础研究更进一步，同时也为缓解吗啡耐受的临床药物的开发提供了一个极好的候选药物靶点。

王韵教授研究室近年来一直致力于蛋白激酶对神经系统功能的研究，获得系列创新进展。该研究室近期还发现，两个蛋白激酶D家族成员PKD1和PKD2是建立和维持神经元极性的关键酶，对神经元极性的调节发挥独特作用。该研究论文2008年8月刚刚发表于The Journal of Neuroscience，并被该刊“This week in the Journal”列为亮点文章给予重点介绍，“Nature China”也推介该论文为Highlights，给以报道。

人物简介：

王韵，医学博士

北京大学基础医学院神经生物学系 副主任

北京大学教授，博士生导师

兼任中国生理学会副秘书长，中国神经科学学会分子神经生物学专业委员会委员，《生理科学进展》常务编委，美国神经科学学会会员，中国疼痛学会会员

科研兴趣及研究方向：

主要从事神经系统细胞信号转导的研究。在科技部“973”项目，教育部全国优秀青年教师奖励基金，教育部“211” II期工程，教育部归国人员启动基金，国家自然科学基金重点及面上项目，北京市自然科学基金及中国中医药管理局资助项目等基金的资助下，目前研究工作的重点主要集中在以下四个方面：

（1）痛与痛觉调制细胞信号转导通路的研究：通过分子生物学，蛋白质生物化学，形态学，电生理学及行为学手段比较研究三种慢性痛模型（慢性炎症痛，神经源性痛及癌症痛）初级感觉神经元和脊髓背角多种痛觉信息分子的作用，以期勾画出在上述三种慢性痛发生、发展过程中起关键作用的信息分子及其可能的信号转导通路。

（2）蛋白激酶系统在中枢神经系统发育及损伤的作用研究：以细胞信号转导为手段，探讨不同的蛋白激酶系统在中枢神经系统发育及损伤的作用。

（3）阿片耐受、依赖及成瘾细胞信号传导通路的研究：采用分子生物学，蛋白质生物化学，形态学，电生理学及行为学等手段在整体、细胞、分子等多个水平深入研究阿片类药物成瘾的神经机制及其可能的信号转导通路。

（4）中枢对外周电刺激频率响应性分子机制的探讨：以细胞信号转导为手段，探讨中枢对不同频率外周电刺激的反应性及部位特异性，以提供中枢神经系统对不同外周刺激处理方式的生物信息学方面的新资料。

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近年发表的代表性论著：（CA：通讯作者）

1. Yin DM, Huang YH, Zhu YB, Wang YCA. Both the establishment and maintenance of neuronal polarity require the activity of protein kinase D in the Golgi apparatus. Journal of Neuroscience, August 27, 2008 • 28(35):8832-8843.

2. Wang Y. The Functional Regulation of TRPV1 and Its Role in Pain Sensitization. Neurochem Res. 2008 Jun 5. [Epub ahead of print]

3. Li Y, Zhang Y, Han JS, Wang YCA. Distinct responses of DREAM to electroacupuncture stimulation with different frequency under physiological and inflammatory conditions in rats. Neurochem Res. 2008 Apr 11. [Epub ahead of print]

4. Zhu H, Yang Y, Zhang H, Han Y, Li Y, Zhang Y, Yin D, He Q, Zhao Z, Blumberg PM, Han J, Wang YCA. Interaction between protein kinase D1 and transient receptor potential V1 in primary sensory neurons is involved in heat hypersensitivity. Pain. 2008 Jul 31;137(3):574-88. Epub 2007 Dec 3.

5. Zhang Y, Li Y, Yang YR, Zhu HH, Han JS, Wang YCA. Distribution of Downstream Regulatory Element Antagonist Modulator (DREAM) in Rat Spinal Cord and Upregulation of Its Expression during Inflammatory Pain. Neurochem Res. 2007 Sep; 32(9):1592-9. Epub 2007 Jun 12.

6. Yang YR, He Y, Zhang Y, Li Y, Li Y, Han Y, Zhu H, Wang YCA. Activation of cyclin-dependent kinase 5 (Cdk5) in primary sensory and dorsal horn neurons by peripheral inflammation contributes to heat hyperalgesia. Pain. 2007 Jan;127(1-2):109-20. Epub 2006 Sep 25.

7. He Y, Li HL, Xie WY, Yang CZ, Yu AC, Wang YCA. The presence of active Cdk5 associated with p35 in astrocytes and its important role in process elongation of scratched astrocyte. Glia. 2007 Feb 12;55(6):573-583 [Epub ahead of print].

8. Wang Y, Xie WY, He Y, Wang M, Yang YR, Zhang Y, Yin DM, Jordan-Sciutto KL, Han JS, Wang Y CA. Role of CDK5 in neuroprotection from serum deprivation by mu-opioid receptor agonist. Exp Neurol.     2006 Dec; 202(2):313-23. Epub 2006 Aug 1.

9. Zhang Y, Xiang B, Li YM, Wang Y, Wang X, Wang YN, Wu LL, Yu GY. Expression and characteristics of vanilloid receptor 1 in the rabbit submandibular gland. Biochem Biophys Res Commun. 2006 Jun 23;345(1):467-73. Epub 2006 May 2.

10. Lazar J, Braun DC, Toth A, Wang Y, Pearce LV, Pavlyukovets VA, Blumberg PM, Garfield  SH, Wincovitch S, Choi HK, Lee J. Kinetics of penetration influence the apparent potency of vanilloids on TRPV1. Mol Pharmacol 2006; Apr; 69(4):1166-1173. Epub; 2006; Jan 17.

11. Wang YCA, Zhang Y, Wang W, Cao Y, Han JS. Effects of synchronous or asynchronous electroacupuncture stimulation with low versus high frequency on spinal opioid release and tail flick nociception. Experimental Neurology 2005; Mar; 192 (1):156-62.

12. Yun WangCA, Noemi Kedei, Qiming Wang, Anna Huppler, Attila Toth, Richard Tran and           Peter M Blumberg CA. The interaction between PKCmu and vanilloid receptor type 1.  Journal of Biological Chemistry 2004; Dec 17; 279(51):53674-82. Epub.

13. Rui-Qing Sun, He-Chun Wang, You Wan, Zheng Jing, Fei Luo, Ji-Sheng Han, and Yun WangCA. Suppression of neuropathic pain by peripheral electrical stimulation in rats: mu-opioid receptor and NMDA receptor implicated. Experimental Neurology 2004; 187: 23-29.

14. Yun Wang, Attila Toth, Richard Tran, Tamas Szabo, Jacqueline D Welter, Peter M Blumberg, Jiyoun Lee, Sang-Uk Kang, Ju-Ok Lim and Jeewoo Lee. High affinity partial agonists of Vanilloid Receptor. Molecular Pharmacology 2003; 64(2): 64(2):325-33.

15. Yun Wang, Tamas Szabo, Jacqueline D, Welter, Attila Toth, Richard Tran, Jiyoun Lee, Sang UK Kang, Young-Ger Suh, Peter M Blumerberg and Jeewoo Lee. High affinity antagonists of the vanilloid receptor. Molecular Pharmacology  2002; 62: 947-956.

16. Wang Y, Wang XM and Han JS. Discrimination between peptide and non-peptide opioid agonists on the transcription of opioid receptors in two cell lines. Life Sci. 2001; 68 (24): 2731-2740.

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17. Wang Y, Huang C, Cao Y and Han JS. Repeated administration of low dose ketamine for the treatment of monoarthritic pain in rat. Life Sci. 2000; 67 (3): 261-267.

18. Chen ZW, Yang K, Wang YCA and Han JS. The metabolic evidence of synergistic interaction between DAMGO and DPDPE on undifferentiated SH-SY5Y cells. NeuroReport 2001; 12(4): 845-849.

19. Chen ZW, Yang K, Wang YCA and Han JS. The metabolic evidence of synergistic effect between ohmefentanyl and [D-Pen2, D-Pen5] enkephalin on differentiated SH-SY5Y cells in humans. Neurosci Lett 2001; 298 (3): 199-202.

20. Sun R, Wang YCA, Zhao CS, Chang JK and Han JS. Changes in Brain content of nocicepin/orphanin FQ and endomorphin 1 in a rat model of neuropathic pain. Neurosci. Lett 2001; 311: 13-16.

21. Huang C, Wang YCA, Chang JK and Han JS. Endomorphin and mu-opioid receptors in mouse brain mediate the analgesic effect induced by 2 Hz but not 100 Hz electroacupuncture stimulation. Neurosci Lett 2000; 294(3): 159-162.

22. M Fang, Y Wang, QH He, YX Sun, LB Deng, XM Wang and JS Han. Glial cell line-derived neurotrophic factor contributes to delayed inflammatory hyperalgesia in adjuvant rat pain model. Neuroscience 2003; 117: 503-512.

23. Tang XQ, Wang Y, Huang ZH, Han JS, Wan Y. Adenovirus-mediated GDNF ameliorates corticospinal neuronal atrophy and motor function deficits in rats with spinal cord injury. NeuroReport 2004; 15: 425-429.

24. Toth A, Wang Y, Kedei N, Tran R, Pearce LV, Kang SU, Jin MK, Choi HK, Lee J, Blumberg PM. Different vanilloid agonists cause different patterns of calcium response in CHO cells heterologously expressing rat TRPV1. Life Sci 2005; May 6; 76(25):2921-32.

25. Attila Toth, Noemi Kedei, Yun Wang and Peter M. Blumberg. Arachidonyl dopamine as a ligand for the vanilloid receptor VR1 of the rat. Life Sci 2003; 73: 487-498.

26. Attila Toth, Noemi Kedei, Tamas Szabo, Yun Wang, and Peter M. Blumberg. Thapsigargin binds to and inhibits the cloned vanilloid receptor-1. Biochemical and Biophysical Research Communication 2002; 293: 777-782.

27. Lee J, Lee J, Kang M, Shin M, Kim JM, Kang SU, Lim JO, Choi HK, Suh YG, Park HG, Oh U, Kim HD, Park YH, Ha HJ, Kim YH, Toth A, Wang Y, Tran R, Pearce LV, Lundberg DJ, Blumberg PM. -(3-Acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl] thiourea Analogues: Novel Potent and High Affinity Antagonists and Partial Antagonists of the Vanilloid Receptor.  J Med Chem 2003; 46(14): 3116-3126.

28. Jeewoo Lee, Sang-Uk Kang, Ju-Ok Lim, Hyun-Kyung Choi, Mi-Kyung Jin, Attila Toth, Larry V. Pearce, Richard Tran, Yun Wang, Tamas Szabo and Peter M Blumberg. N-[4-(Methylsulfonylamino)benzyl]thiourea analogues as vanilloid receptor antagonists: analysis of structure–activity relationships for the ‘C-Region’. Bioorganic & Medicinal Chemistry 2004; 12: 371–385.

29. Lee J, Kim SY, Lee J, Kang M, Kil MJ, Choi HK, Jin MK, Wang Y, Toth A, Pearce LV, Lundberg DJ, Tran R, Blumberg PM. Analysis of structure-activity relationships with the N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea template for vanilloid receptor 1 antagonism. Bioorg Med Chem 2004; 12(13): 3411-3420.

30. Lee J, Kang SU, Choi HK, Lee J, Lim JO, Kil MJ, Jin MK, Kim KP, Sung JH, Chung SJ, Ha HJ, Kim YH, Pearce LV, Tran R, Lundberg DJ, Wang Y, Toth A, Blumberg PM. Analysis of structure-activity relationships for the 'B-region' of -(3-acyloxy-2-benzylpropyl)-N(')-[4-(methylsulfonylamino)benzyl]thiourea analogues as vanilloid receptor antagonists: discovery of an N-hydroxythiourea analogue with potent analgesic activity. Bioorg Med Chem Lett 2004; 14(9):2291-2297.

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31. Lee J, Kang SU, Kil MJ, Shin M, Lim JO, Choi HK, Jin MK, Kim SY, Kim SE, Lee YS, Min KH, Kim YH, Ha HJ, Tran R, Welter JD, Wang Y, Szabo T, Pearce LV, Lundberg DJ, Toth A, Pavlyukovets VA, Morgan MA, Blumberg PM. Analysis of structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues as TRPV1 antagonists. Bioorg Med Chem Lett. 2005; Sep 15; 15(18):4136-4142.

32. Lee J, Jin MK, Kang SU, Kim SY, Lee J, Shin M, Hwang J, Cho S, Choi YS, Choi HK, Kim SE, Suh YG, Lee YS, Kim YH, Ha HJ, Toth A, Pearce LV, Tran R, Szabo T, Welter JD, Lundberg DJ, Wang Y, Lazar J, Pavlyukovets VA, Morgan MA, Blumberg PM. Analysis of structure-activity relationships for the 'B-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]-thiourea analogues as TRPV1 antagonists. Bioorg Med Chem Lett 2005; Sep 15; 15(18):4143-4150.

33. Huang C, Wang Y, Han JS, Wan Y. Characteristics of electroacupuncture-induced analgesia in mice: variation with strain, frequency, intensity and opioid involvement. Brain Res 2002; 945(1): 20-25.

34. Tang XQ, Wang Y, Han JS and Wan Y. Adenovirus-mediated GDNF protects cultured motoneurons from glutamate injury. Neuroreport  2001; 12: 3073-3076.

35. Sun RQ, Zhao CS, Wang HJ, Jing Z, Wang W, Yang K, Wang Y, Chang JK and Han JS. Nocistatin, a peptide reversing acute and chronic morphine tolerance. Neuroreport  2001; 12 (8):1789-1792.

36. Fang M, Wang Y, Liu HX, Liu XS and Han JS. Decreased GDNF expression in dorsal spinal cord of unilateral arthritic rat. NeuroReport 2000; 11 (4): 737-741.