title: Mechanisms of the inhibition of nuclear factor-κB by morphine in neuronal cells.
abstract: Opioids potently modulate neuronal functions, for example, by regulating the activity of transcription factors. Here, we investigated the effect of morphine on the activity of the transcription factor nuclear factor κB (NF-κB). Establishing cellular models for our investigations, we demonstrated that NF-κB mediated the tumor necrosis factor (TNF)-induced transcription of the cannabinoid receptor type 1 gene in primary fetal striatal neurons from rats and the human neuroblastoma cell line SH SY5Y. The activity of NF-κB in these models was strongly inhibited by morphine, which was achieved by a marked up-regulation of the inhibitor of nuclear factor-κB (IκB). The opioid-induced up-regulation of IκB was dependent on the transcription factors NF-κB itself and activator protein-1 (AP-1). In fact, stimulation of the cells with morphine resulted in a transient activation of NF-κB and a strong induction of c-Fos, one of the constituents of AP-1. This resulted in IκB levels significantly exceeding the basal, constitutive levels of IκB. These data, together with experiments in which AP-1 and IκB were down-regulated by decoy oligonucleotides and siRNA, suggest that the morphine-induced activation of AP-1 and the subsequent overexpression of IκB are key factors in the inhibition of NF-κB by the drug. In contrast, stimulation of primary neurons from rats and SH SY5Y cells with TNF, which is a classic activator of NF-κB, resulted in a resynthesis of IκB, in which the basal levels of IκB were restored only but did not result in an activation of AP-1 and overexpression of IκB.
authors.affiliation: Department of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Börner
authors.forename: Volker
authors.initials: V
authors.lastname: Höllt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kraus
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D017930:Genes, Reporter; D006801:Humans; D009020:Morphine / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D017931:DNA Primers; D016328:NF-kappa B; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D009020:Morphine