RT Journal Article
SR Electronic
T1 Mechanisms of the Inhibition of NF−κB by Morphine in Neuronal Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.111.076620
DO 10.1124/mol.111.076620
A1 Christine Borner
A1 Volker Hollt
A1 Jurgen Kraus
YR 2012
UL http://molpharm.aspetjournals.org/content/early/2012/01/18/mol.111.076620.abstract
AB 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.