Activation of the nociceptin receptor stably expressed in Chinese hamster ovary cells induced a transient mitogen-activated protein kinase (MAPK) activation, via pertussis toxin-sensitive G-proteins, The nociceptin receptor-mediated MAPK activation was partially blocked by down-regulation or inhibition of protein kinase C, and suppressed by pretreatment with a phosphatidylcholine-specific phospholipase C inhibitor, D609, Furthermore, a tyrosine protein kinase inhibitor, genistein, and phosphatidylinositol 3-kinase inhibitors, wortmannin and LY294002, affected the nociceptin-induced MAPK activity. The nociceptin-induced MAPK activation may lead to activation of phospholipase A(2) and induce changes in gene expression. (C) 1997 Federation of European Biochemical Societies.