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A non-peptide substance P antagonist (CP-96,345) inhibits morphine-induced NF-kappa B promoter activation in human NT2-N neurons.

Journal of neuroscience research (2004-01-27)
Xu Wang, Steven D Douglas, Kathryn G Commons, David E Pleasure, Jianping Lai, Chun Ho, Peter Bannerman, Marge Williams, Wenzhe Ho
RÉSUMÉ

Opioids and the neuropeptide substance P (SP) modulate the expression of inflammatory cytokines and chemokines, which are under the control of nuclear factor kappaB (NF-kappaB). We investigated whether the neurokinin-1 receptor (SP receptor) pathway is biologically involved in morphine-mediated modulation of NF-kappaB 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-kappaB promoter-directed luciferase activity in NT2-N neurons. DAMGO, a selective mu-opioid receptor agonist, also induced NF-kappaB promoter activation. The induced activation of NF-kappaB 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-kappaB 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-kappaB 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-kappaB expression and therefore may be an important participant in the effect of morphine on immune responses in the central nervous system.

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CP-96345, ≥98% (HPLC)