The modulation exerted by nociceptin/orphanin FQ (NC) on noradrenaline (NE) release in rodent cerebral cortex slices and synaptosomes was studied.Rat, mouse and guinea-pig cortical slices and synaptosomes were preincubated with 0.1 μM [3H]-NE and superfused. NE release was evoked by 2 min of electrical (3 Hz) stimulation in slices and by 1 min pulse of 10 mM KCl in synaptosomes.In rat cortical slices, 0.01–3 μM NC reduced the evoked [3H]-NE efflux (Emax−54%), with a bell-shaped concentration-response curve, which regained its monotonic nature in the presence of either 0.1 μM naloxone (NX) or 30 μM bicuculline. In synaptosomes, the NC effect curve was sygmoidal in shape and reached a plateau at 1 μM concentration.In the rat, both 1 μM [Phe1ψ(CH2-NH)Gly2]NC(1-13)NH2 and 10 μM [Nphe1]NC(1-13)NH2 (NPhe) antagonised NC-induced inhibition, without per se modifying [3H]-NE efflux. The effects of 0.3–1 μM NC concentrations were partially prevented by 1 μM NX; 1 μM D-Phe-Cys-Thr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) was also an effective antagonist, but 0.1 μM norbinaltorphimine was not.In the mouse cerebral cortex, NC-induced inhibition of NE release (pEC50 6.87, Emax−61%, in the slices) was prevented by Nphe but was NX-insensitive. In guinea-pig cortical slices, NC effect (pEC50 6.22, Emax−38%) was prevented by Nphe, but was NX-insensitive.These findings demonstrate that NC inhibits NE release from rodent cerebral cortex via presynaptically located ORL1 receptors. In the rat, μ opioid and GABAA receptors are involved as well.