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学科主题: 基础医学
题名:
Disruption of Cdk5-Associated Phosphorylation of Residue Threonine-161 of the delta-Opioid Receptor: Impaired Receptor Function and Attenuated Morphine Antinociceptive Tolerance
作者: Xie, Wei-Yan1; He, Yi1; Yang, Yan-Rui1; Li, Ya-Fang1; Kang, Kai1; Xing, Bao-Ming1; Wang, Yun1
刊名: JOURNAL OF NEUROSCIENCE
发表日期: 2009-03-18
DOI: 10.1523/JNEUROSCI.0415-09.2009
卷: 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
所属项目编号: 30371635 ; 303330026 ; 30770703 ; 30830044 ; 7072040 ; 20060001121
项目资助者: National Natural Science Foundation of China ; Beijing Natural Science Foundation ; Specialized Research Fund for Doctoral Program of Higher Education
WOS记录号: WOS:000264342100022
Citation statistics:
内容类型: 期刊论文
版本: 出版稿
URI标识: http://ir.bjmu.edu.cn/handle/400002259/53109
Appears in Collections:基础医学院_神经生物学系_期刊论文

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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

Recommended Citation:
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.
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