A Non-Peptide Substance P Antagonist (CP-96,345) Inhibits Morphine-Induced NF-κB Promoter Activation in Human NT2-N Neurons

Xu Wang, Steven D. Douglas, Kathryn G. Commons, David E Pleasure, Jianping Lai, Chun Ho, Peter Bannerman, Marge Williams, Wenzhe Ho

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Opioids and the neuropeptide substance P (SP) modulate the expression of inflammatory cytokines and chemokines, which are under the control of nuclear factor κB (NF-κB). We investigated whether the neurokinin-1 receptor (SP receptor) pathway is biologically involved in morphine-mediated modulation of NF-κB promoter activation in a human neuronal cell line (NT2-N) that expresses both the mu-opioid receptor (MOR) and the SP receptor. Morphine significantly enhanced NF-κB promoter-directed luciferase activity in NT2-N neurons. DAMGO, a selective mu-opioid receptor agonist, also induced NF-κB promoter activation. The induced activation of NF-κB promoter by morphine or DAMGO was abolished not only by naltrexone (a opioid receptor antagonist) and CTAP (a selective, competitive mu-opioid receptor antagonist), but also by CP-96,345, a non-peptide SP receptor antagonist. Investigation of the mechanism responsible for morphine-induced activation of NF-κB promoter in NT2-N neurons demonstrated that morphine activates the SP promoter and induces SP expression in these cells. We also observed that SP activated NF-κB promoter and that CP-96,345 downregulated the expression of endogenous SP. Furthermore, dual immunofluorescent labeling revealed that there is co-expression of NK-1R and MOR in the processes of NT-2N neurons. These results suggest that morphine, by activating MOR, engages a positive feedback loop between NK-1R and SP. Activation of NK-1R could then impact NF-κB expression and therefore may be an important participant in the effect of morphine on immune responses in the central nervous system.

Original languageEnglish (US)
Pages (from-to)544-553
Number of pages10
JournalJournal of Neuroscience Research
Volume75
Issue number4
DOIs
StatePublished - Feb 15 2004
Externally publishedYes

Keywords

  • DAMGO
  • Mu-opioid receptor
  • NK-1R
  • SP promoter

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint

Dive into the research topics of 'A Non-Peptide Substance P Antagonist (CP-96,345) Inhibits Morphine-Induced NF-κB Promoter Activation in Human NT2-N Neurons'. Together they form a unique fingerprint.

Cite this