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 （...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.展开更多
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)
文摘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.
