LAUSR

&NA; Glioblastoma is among the most aggressive brain tumors and has an exceedingly poor prognosis. Recently, the importance of the tumor microenvironment in glioblastoma cell growth and progression has been emphasized. Toll‐like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and endogenous ligands originating from dying cells or the extracellular matrix involved in host defense and in inflammation. G‐protein coupled receptors (GPCRs) have gained interest in anti‐tumor drug discovery due to the role that they directly or indirectly play by transactivating other receptors, causing cell migration and proliferation. A proteomic analysis showed that the nociceptin receptor (NOPr) is among the GPCRs significantly expressed in glioblastoma cells, including U87 cells. We describe a novel role of the peptide nociceptin (N/OFQ), the endogenous ligand of the NOPr that counteracts cell migration, proliferation and increase in IL‐1&bgr; mRNA elicited by LPS via TLR4 in U87 glioblastoma cells. Signaling pathways through which N/OFQ inhibits LPS‐mediated cell migration and elevation of [Ca2+]i require &bgr;‐arrestin 2 and are sensitive to TNFR‐associated factor 6, c‐Src and protein kinase C (PKC). LPS‐induced cell proliferation and increase in IL‐1&bgr; mRNA are counteracted by N/OFQ via &bgr;‐arrestin 2, PKC and extracellular signal‐regulated kinase 1/2; furthermore, the contributions of the transcription factors NF‐kB and AP‐1 were investigated. Independent of LPS, N/OFQ induces a significant increase in cell apoptosis. Contrary to what was observed in other cell models, a prolonged exposure to this endotoxin did not promote any tolerance of the cellular effects above described, including NOPr down‐regulation while N/OFQ loses its inhibitory role.