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Nucleic Acids Res. 2014 Dec 1;42(21):13012-25. doi: 10.1093/nar/gku1016. Epub 2014 Oct 31.

Morphine drives internal ribosome entry site-mediated hnRNP K translation in neurons through opioid receptor-dependent signaling.

Author information

1
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
2
The PhD Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.
3
Graduate Institute of Biotechnology, Chinese Culture University, Taipei 11114, Taiwan, ROC.
4
Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, MN 55455, USA.
5
Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
6
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC bau9763@bp.nhri.org.tw.

Abstract

Heterogeneous nuclear ribonucleoprotein K (hnRNP K) binds to the promoter region of mu-opioid receptor (MOR) to regulate its transcriptional activity. How hnRNP K contributes to the analgesic effects of morphine, however, is largely unknown. We provide evidence that morphine increases hnRNP K protein expression via MOR activation in rat primary cortical neurons and HEK-293 cells expressing MORs, without increasing mRNA levels. Using the bicistronic reporter assay, we examined whether morphine-mediated accumulation of hnRNP K resulted from translational control. We identified potential internal ribosome entry site elements located in the 5' untranslated regions of hnRNP K transcripts that were regulated by morphine. This finding suggests that internal translation contributes to the morphine-induced accumulation of hnRNP K protein in regions of the central nervous system correlated with nociceptive and antinociceptive modulatory systems in mice. Finally, we found that down-regulation of hnRNP K mediated by siRNA attenuated morphine-induced hyperpolarization of membrane potential in AtT20 cells. Silencing hnRNP K expression in the spinal cord increased nociceptive sensitivity in wild-type mice, but not in MOR-knockout mice. Thus, our findings identify the role of translational control of hnRNP K in morphine-induced analgesia through activation of MOR.

PMID:
25361975
PMCID:
PMC4245930
DOI:
10.1093/nar/gku1016
[Indexed for MEDLINE]
Free PMC Article

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