☆ 4.6 Article

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

NEUROSCIENCE BULLETIN (2012)

Journal

NEUROSCIENCE BULLETIN

Volume 28, Issue 2, Pages 182-192

Publisher

SPRINGER

DOI: 10.1007/s12264-012-1216-8

Keywords

inflammatory hypersensitivity; cyclin-dependent kinase 5; delta-opioid receptor; morphine tolerance

Funding

National Natural Science Foundation of China [30830044, 30925015, 30800330, 81161120497]
Beijing Natural Science Foundation [7092061]
Specialized Research Fund for Doctoral Program of Higher Education Grants, China [200800011028, 20060001121]

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Abstract

Objective Our previous study identified Threonine 161 (Thr-161), located in the second intracellular loop of the delta-opioid receptor (DOR), as the only consensus phosphorylation site for cyclin-dependent kinase 5 (Cdk5). 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 inflammatory 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. Intrathecal 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 mu-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.

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