TY - JOUR T1 - Mechanisms of the Inhibition of NF−κB by Morphine in Neuronal Cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.076620 SP - mol.111.076620 AU - Christine Borner AU - Volker Hollt AU - Jurgen Kraus Y1 - 2012/01/18 UR - http://molpharm.aspetjournals.org/content/early/2012/01/18/mol.111.076620.abstract N2 - 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 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 upregulation of I-κB, the inhibitor of NF-κB. The opioid-induced upregulation of I-κB was dependent on the transcription factors NF-κB itself and 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 I-κB levels significantly exceeding the basal, constitutive levels of I-κB. These data, together with experiments, in which AP-1 and I-κB were down-regulated by decoy oligonucleotides and siRNA, suggest that the morphine-induced activation of AP-1, and the subsequent overexpression of I-κB 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 I-κB, in which the basal levels of I-κB were restored, only, but not in an activation of AP-1 and overexpression of I-κB. ER -