The purpose of the present study was to investigate the effects of L-N5-(1-iminoethyl)ornithine hydrochloride (L-NIO), an inhibitor of nitric oxide (NO) formation, and [Phe1-psi(CH2NH)-Gly2]Nociceptin(1-13)-NH2 (Phe-NOC), a nociceptin receptor antagonist, on the systemic vasodepressor response to nociceptin in the anesthetized rat. The systemic vasodepressor response to bolus intravenous (i.v.) injections of nociceptin was significantly reduced by L-NIO and Phe-NOC. The present data suggest activation of nociceptin receptors dilates the systemic vascular bed through a NO-dependent pathway. These data also demonstrate Phe-NOC is an efficacious and selective nociceptin receptor antagonist in vivo.