Regulation of nociceptin/orphanin FQ gene expression in astrocytes by ceramide

Ceramide is generated in response to inflammatory mediators and oxidative stress. Since these stimuli dramatically increase nociceptin/orphanin FQ (N/OFQ) gene expression in astrocytes we evaluated the regulation of N/OFQ by ceramide and the signaling mechanisms involved. We found that ceramide induced N/OFQ mRNA levels 22-fold after 24 h. In astrocytes ceramide stimulated the JNK, p38 and ERK MAP kinase pathways and also led to the activation of the transcription factors CREB and NFkappaB. Using specific inhibitors of signaling pathways we determined that N/OFQ gene induction is mediated by ERK and p38 MAP kinases. ERK activation may be induced by protein kinase C and it leads to CREB phosphorylation. The NFkappaB pathway also appears to be crucial for ceramide-induced N/OFQ gene expression. (C) 2002 Lippincott Williams Wilkins.