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| △-阿片受体苏氨酸残基-161的Cdk5相关性磷酸化破坏：受体功能受损和吗啡镇痛耐受的减弱 |
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| Disruption of Cdk5-associated phosphorylation of residue threonine-161 of the δ-opioid receptor: Impaired receptor function and attenuated morphine antinociceptive tolerance |
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| Xie W.-Y., He Y., Yang Y.-R., Li Y.-F., Kang K., Xing B.-M., Wang Y. 2009/5/29 18:40:20 |
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Journal of Neuroscience, 2009, Volume 29, Issue 11
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| 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 δ-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 μ-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. Copyright © 2009 Society for Neuroscience. |
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| Correspondence Address: Wang, Y.; Neuroscience Research Institute, Department of Neurobiology, Peking University, 38 Xueyuan Road, Beijing 100083, China; email: wangy66@bjmu.edu.cn |
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 疾病资源中心
摘自：《西氏内科学》，第23版
患者女性，21岁，因干咳、间歇性气促2个月到急诊科就诊。开始症状为上呼吸道感染引起的鼻塞、流涕和咳嗽。医生检查后开了抗生素。服药后鼻部症状缓解，但仍有轻微干咳和呼吸困难。其他症状包括疲劳和焦虑。否认发热、体重减轻、胸痛、端坐呼吸、气喘、鼻后滴漏、胃灼热以及神经系统症状。
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