Inhibition of c-Jun NH2-terminal kinase stimulates mu opioid receptor expression via p38 MAPK-mediated nuclear NF-κB activation in neuronal and non-neuronal cells

Yadav Wagley, Cheol Kyu T Hwang, Hong Yiou Lin, Angel F Y Kam, Ping-Yee Law, Horace H Loh, Li-Na Wei

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Despite its potential side effects of addiction, tolerance and withdrawal symptoms, morphine is widely used for reducing moderate and severe pain. Previous studies have shown that the analgesic effect of morphine depends on mu opioid receptor (MOR) expression levels, but the regulatory mechanism of MOR is not yet fully understood. Several in vivo and in vitro studies have shown that the c-Jun NH2-terminal kinase (JNK) pathway is closely associated with neuropathic hyperalgesia, which closely resembles the neuroplastic changes observed with morphine antinociceptive tolerance. In this study, we show that inhibition of JNK by SP600125, its inhibitory peptide, or JNK-1 siRNA induced MOR at both mRNA and protein levels in neuronal cells. This increase in MOR expression was reversed by inhibition of the p38 mitogen-activated protein kinase (MAPK) pathway, but not by inhibition of the mitogen-activated protein/extracellular signal-regulated kinase (MEK) pathway. Further experiments using cell signaling inhibitors showed that MOR upregulation by JNK inhibition involved nuclear factor-kappa B (NF-κB). The p38 MAPK dependent phosphorylation of p65 NF-κB subunit in the nucleus was increased by SP600125 treatment. We also observed by chromatin immunoprecipitation (ChIP) analysis that JNK inhibition led to increased bindings of CBP and histone-3 dimethyl K4, and decreased bindings of HDAC-2, MeCP2, and histone-3 trimethyl K9 to the MOR promoter indicating a transcriptional regulation of MOR by JNK inhibition. All these results suggest a regulatory role of the p38 MAPK and NF-κB pathways in MOR gene expression and aid to our better understanding of the MOR gene regulation.

Original languageEnglish (US)
Pages (from-to)1476-1488
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number6
DOIs
StatePublished - Jun 2013

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health [Grants DA000564 , DA001583 , DA011806 , K05-DA070554 (HHL), DA011190 , DA013926 (LW)]; and by the A&F Stark Fund of the Minnesota Medical Foundation . We thank Dr. Tracy Kuhlman for editorial assistance with the manuscript. The authors declare no conflict of interest.

Keywords

  • JNK
  • MAPK
  • Mu opioid receptor
  • NF-κB

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