title: Morphine drives internal ribosome entry site-mediated hnRNP K translation in neurons through opioid receptor-dependent signaling.
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.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Pin-Tse
authors.initials: PT
authors.lastname: Lee
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Po-Kuan
authors.initials: PK
authors.lastname: Chao
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Li-Chin
authors.initials: LC
authors.lastname: Ou
authors.affiliation: The PhD Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Chuang
authors.affiliation: Graduate Institute of Biotechnology, Chinese Culture University, Taipei 11114, Taiwan, ROC.
authors.forename: Yen-Chang
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Hsiao-Fu
authors.initials: HF
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, MN 55455, USA.
authors.forename: Ping-Yee
authors.initials: PY
authors.lastname: Law
authors.affiliation: Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, MN 55455, USA.
authors.forename: Horace H
authors.initials: HH
authors.lastname: Loh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.affiliation: Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC bau9763@bp.nhri.org.tw.
authors.forename: Shiu-Hwa
authors.initials: SH
authors.lastname: Yeh
mesh_terms: D020121:5' Untranslated Regions / Q000187:drug effects*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D017124:Conserved Sequence; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D057809:HEK293 Cells; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D059225:Nociception; D014176:Protein Biosynthesis / Q000187:drug effects*; D051381:Rats; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020121:5' Untranslated Regions; D000701:Analgesics, Opioid; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine