Nociceptin/orphanin FQ (NC), the endogenous ligand for the G-protein coupled nociceptin receptor (NCR), has a modulatory role in various physiological processes including neuro-transmitter release. We have examined the effects of NC, the analogues NC(1–13)NH2and [F/G]NC(1–13)NH2and the competitive antagonist [Nphe1]NC(1–13)NH2(Nphe1) on glutamate efflux during an acute simulated ischaemic challenge in rat cerebrocortical slices. The increase in glutamate efflux seen with ischaemia was inhibited by NC (EC50250 nM). At micromolar concentrations, the analogues were found to have a similar effect on glutamate efflux compared to NC. In all cases, inhibition of glutamate efflux was abolished by Nphe1(30 μM). These results suggest a neuroprotective action for NC.