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学科主题基础医学
Disruption of Cdk5-Associated Phosphorylation of Residue Threonine-161 of the delta-Opioid Receptor: Impaired Receptor Function and Attenuated Morphine Antinociceptive Tolerance
Xie, Wei-Yan1; He, Yi1; Yang, Yan-Rui1; Li, Ya-Fang1; Kang, Kai1; Xing, Bao-Ming1; Wang, Yun1
刊名JOURNAL OF NEUROSCIENCE
2009-03-18
DOI10.1523/JNEUROSCI.0415-09.2009
29期:11页:3551-3564
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Neurosciences
研究领域[WOS]Neurosciences & Neurology
关键词[WOS]CYCLIN-DEPENDENT KINASE-5 ; DORSAL-ROOT GANGLIA ; RAT SPINAL-CORD ; KNOCK-OUT MICE ; PHYSICAL-DEPENDENCE ; OPIATE RECEPTORS ; MU-RECEPTOR ; IN-VIVO ; TRAFFICKING ; ANALGESIA
英文摘要

Morphine is the most commonly used and most effective analgesic in the clinic. However, its use is limited by the tolerance. Evidence indicates that the delta-opioid receptor (DOR) is essential for morphine antinociceptive tolerance; however, their underlying mechanisms are poorly understood. Here, we show that cyclin-dependent kinase 5 (Cdk5), activated in morphine antinociceptive tolerance, directly phosphorylates DOR at Thr-161 in DRG neurons. Cdk5 was found to phosphorylate Thr-161 in the second loop of DOR, but not the corresponding residue in the mu-opioid receptor (MOR). Phosphorylation at Thr-161 is required for normal cell surface expression of DOR, and the formation of DOR-MOR heterodimers. Our studies indicated that inhibition of Cdk5 activity or overexpression of a DOR mutant lacking the Cdk5 phosphorylation site displayed relatively low cell surface expression and relatively low abilities to form heterodimers of DOR and MOR; intrathecal delivery of a construct expressing the T161A mutant of DOR attenuated morphine antinociceptive tolerance in rats, suggesting that Thr-161 phosphorylation of DOR contributed to Cdk5-mediated morphine antinociceptive tolerance. Furthermore, an engineered Tat fusion-interfering peptide corresponding to the second intracellular loop of DOR (Tat-DOR-2L), reduced the cell surface expression of DOR, disrupted the formation of DOR-MOR heterodimers, and significantly attenuated the development of morphine antinociceptive tolerance after intrathecal injection. The present study indicates that Cdk5-mediated phosphorylation of DOR at Thr-161 plays a crucial role in the development of morphine tolerance and suggests the possibility of targeting DOR phosphorylation at Thr-161 to attenuate morphine antinociceptive tolerance during pain management.

语种英语
WOS记录号WOS:000264342100022
项目编号30371635 ; 303330026 ; 30770703 ; 30830044 ; 7072040 ; 20060001121
资助机构National Natural Science Foundation of China ; Beijing Natural Science Foundation ; Specialized Research Fund for Doctoral Program of Higher Education
引用统计
被引频次:37[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
版本出版稿
条目标识符http://ir.bjmu.edu.cn/handle/400002259/53109
专题北京大学基础医学院_神经生物学系
作者单位1.Peking Univ, Neurosci Res Inst, Hlth Sci Ctr, Beijing 100083, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Dept Neurobiol, Key Lab Neurosci,Minist Educ & Hlth, Beijing 100083, Peoples R China
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GB/T 7714
Xie, Wei-Yan,He, Yi,Yang, Yan-Rui,et al. Disruption of Cdk5-Associated Phosphorylation of Residue Threonine-161 of the delta-Opioid Receptor: Impaired Receptor Function and Attenuated Morphine Antinociceptive Tolerance[J]. JOURNAL OF NEUROSCIENCE,2009,29(11):3551-3564.
APA Xie, Wei-Yan.,He, Yi.,Yang, Yan-Rui.,Li, Ya-Fang.,Kang, Kai.,...&Wang, Yun.(2009).Disruption of Cdk5-Associated Phosphorylation of Residue Threonine-161 of the delta-Opioid Receptor: Impaired Receptor Function and Attenuated Morphine Antinociceptive Tolerance.JOURNAL OF NEUROSCIENCE,29(11),3551-3564.
MLA Xie, Wei-Yan,et al."Disruption of Cdk5-Associated Phosphorylation of Residue Threonine-161 of the delta-Opioid Receptor: Impaired Receptor Function and Attenuated Morphine Antinociceptive Tolerance".JOURNAL OF NEUROSCIENCE 29.11(2009):3551-3564.
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