title: A non-peptide substance P antagonist (CP-96,345) inhibits morphine-induced NF-kappa B promoter activation in human NT2-N neurons.
abstract: 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.
authors.affiliation: Division of Immunologic and Infectious Diseases, Joseph Stokes Jr. Research Institute of The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Steven D
authors.initials: SD
authors.lastname: Douglas
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Commons
authors.forename: David E
authors.initials: DE
authors.lastname: Pleasure
authors.forename: Jianping
authors.initials: J
authors.lastname: Lai
authors.forename: Chun
authors.initials: C
authors.lastname: Ho
authors.forename: Peter
authors.initials: P
authors.lastname: Bannerman
authors.forename: Marge
authors.initials: M
authors.lastname: Williams
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Ho
mesh_terms: D001713:Biphenyl Compounds / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D006801:Humans; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001713:Biphenyl Compounds; D016328:NF-kappa B; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D013373:Substance P; D009020:Morphine; C066892:CP 96345