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

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


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / drug effects*
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Base Sequence
  • Brain / drug effects
  • Brain / metabolism
  • Cells, Cultured
  • Conserved Sequence
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoprotein K / biosynthesis*
  • Heterogeneous-Nuclear Ribonucleoprotein K / genetics
  • Humans
  • Mice
  • Morphine / pharmacology*
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nociception
  • Protein Biosynthesis / drug effects*
  • Rats
  • Receptors, Opioid, mu / metabolism*
  • Ribosomes / metabolism
  • Signal Transduction
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Up-Regulation


  • 5' Untranslated Regions
  • Analgesics, Opioid
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Heterogeneous-Nuclear Ribonucleoprotein K
  • Narcotic Antagonists
  • Receptors, Opioid, mu
  • Naloxone
  • Morphine