A non-peptide substance P antagonist (CP-96,345) inhibits morphine-induced NF-kappa B promoter activation in human NT2-N neurons.
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.
Wang
Xu
X
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.
Douglas
Steven D
SD
Commons
Kathryn G
KG
Pleasure
David E
DE
Lai
Jianping
J
Ho
Chun
C
Bannerman
Peter
P
Williams
Marge
M
Ho
Wenzhe
W
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
D001713:Biphenyl Compounds; D016328:NF-kappa B; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D013373:Substance P; D009020:Morphine; C066892:CP 96345