Nociceptin (1 μg/mL) significantly prevents LPS (10 ng/mL)-stimulated cell migration whereas it is ineffective when added alone. Nociceptin (1 nM-10 μM) elicits a concentration-dependent blockade of LPS-mediated cell migration, with a maximal effect at 1 and 10 μM. Nociceptin counteracts LPS-induced elevation of IL-1β mRNA levels. Nociceptin (1 μM) and NNC 55-0396 induce apoptotic cell death in U87 cells. Nociceptin (1 μM) counteracts LPS-induced [Ca 2+ ]i increase in U87 cells via β-arrestin 2. Nociceptin counteracts the LPS-induced phosphorylation of PKC and ERK in U87 cells. Nociceptin inhibits the LPS-mediated transcriptional activation of NF-kB and AP-1 reporter genes.