Disruption of δ-opioid receptor phosphorylation at Threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity  

作　　者：Hai-Jing Chen Wei-Yan Xie Fang Hu Ying Zhang Jun Wang Yun Wang 

机构地区：[1]Neuroscience Research Institute, Peking University, Department of Neurobiology, School of Basic Medical Sciences,Peking University, Beij＇ing 100191, China [2]Beijing Neurosurgical Institute, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing 100050, China [3]Department of Anatomy and Histology, School of Basic Medical Sciences, Peking University, Beo＇ing 100191, China

出　　处：《Neuroscience Bulletin》2012年第2期182-192,共11页神经科学通报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China (30830044, 30925015, 30800330, and 81161120497);Beijing Natural Science Foundation (7092061);Specialized Research Fund for Doctoral Program of Higher Education Grants, China (200800011028 and 20060001121)

摘　　要：Objective Our previous study identified Threonine 161 （Thr-161）, located in the second intracellular loop of the 6-opioid receptor （DOR）, as the only consensus phosphorylation Cdte for cyclin-dqpendent kinase 5 （CdkS）. The aim of this study was to assess the function of DOR phosphorylation by Cdk5 in complete Freund＇s adjuvant （CFA）-induced inflammatory pain and morphine tolerance. Methods Dorsal root ganglion （DRG） neurons of rats with CFA-induced in- flammatory pain were acutely dissociated and the biotinylation method was used to explore the membrane localization of phosphorylated DOR at Thr-161 （pThr-161-DOR）, and paw withdrawal latency was measured after intrathecal delivery of drugs or Tat-peptide, using a radiant heat stimulator in rats with CFA-induced inflammatory pain. Results Both the total amount and the surface localization of pThr-161-DOR were significantly enhanced in the ipsilateral DRG following CFA injection. lntrathecal delivery of the engineered Tat fusion-interefering peptide corresponding to the second intracellular loop of DOR （Tat-DOR-2L） increased inflammatory hypersensitivity, and inhibited DOR- but not μ-opioid receptor-mediated spinal analgesia in CFA-treated rats. However, intrathecal delivery of Tat-DOR-2L postponed morphine antinociceptive tolerance in rats with CFA-induced inflammatory pain. Conclusion Phosphorylation of DOR at Thr-161 by Cdk5 attenuates hypersensitivity and potentiates morphine tolerance in rats with CFA-induced inflammatory pain, while disruption of the phosphorylation of DOR at Thr- 161 attenuates morphine tolerance.Objective Our previous study identified Threonine 161 （Thr-161）, located in the second intracellular loop of the 6-opioid receptor （DOR）, as the only consensus phosphorylation Cdte for cyclin-dqpendent kinase 5 （CdkS）. The aim of this study was to assess the function of DOR phosphorylation by Cdk5 in complete Freund＇s adjuvant （CFA）-induced inflammatory pain and morphine tolerance. Methods Dorsal root ganglion （DRG） neurons of rats with CFA-induced in- flammatory pain were acutely dissociated and the biotinylation method was used to explore the membrane localization of phosphorylated DOR at Thr-161 （pThr-161-DOR）, and paw withdrawal latency was measured after intrathecal delivery of drugs or Tat-peptide, using a radiant heat stimulator in rats with CFA-induced inflammatory pain. Results Both the total amount and the surface localization of pThr-161-DOR were significantly enhanced in the ipsilateral DRG following CFA injection. lntrathecal delivery of the engineered Tat fusion-interefering peptide corresponding to the second intracellular loop of DOR （Tat-DOR-2L） increased inflammatory hypersensitivity, and inhibited DOR- but not μ-opioid receptor-mediated spinal analgesia in CFA-treated rats. However, intrathecal delivery of Tat-DOR-2L postponed morphine antinociceptive tolerance in rats with CFA-induced inflammatory pain. Conclusion Phosphorylation of DOR at Thr-161 by Cdk5 attenuates hypersensitivity and potentiates morphine tolerance in rats with CFA-induced inflammatory pain, while disruption of the phosphorylation of DOR at Thr- 161 attenuates morphine tolerance.

关 键 词：inflammatory hypersensitivity cyclin-dependent kinase 5 6-opioid receptor morphine tolerance 

分 类 号：Q95-3[生物学—动物学] Q432