Central injections of nocistatin or its C-terminal hexapeptide exert anxiogenic-like effect on behaviour of mice in the plus-maze test

1. Nocistatin (NST) antagonizes several actions of nociceptin/orphanin FQ (N/OFQ), but acts on distinct receptors. As N/OFQ exerts anxiolytic-like actions in various tests, its behavioural actions in the elevated plus-maze (EPM) test were compared with those of bovine NST. 2. Five minutes after i.c.v. treatment, mice were placed on the EPM for 5 min and entries into and time spent on open and closed arms were recorded alongside other parameters. 3. NST (0.1-3 pmol) reduced percentages of entries into (control 39.6±3.1%, peak effect at 1 pmol NST 8.5±2.9%) and time spent on open arms (control 30.8±2.3%, NST 2.7±1.5%). The C-terminal hexapeptide of NST CNST-C6; 0.01-10 pmol) closely mimicked these actions of NST, with peak effects at 0.1 pmol. 4. N/OFQ (1-100 pmol) increased percentages of entries into (control 38.5±3.4%; peak effect at 10 pmol N/OFQ 67.9±4.9%) and time spent on open arms (control 32.0±3.8%; N/OFQ 74.9±5.8%). Closed arm entries, an index of locomotor activity, were unchanged by all peptides. 5. Effects of NST or NST-C6, but not N/OFQ, were still detectable 15 min after injection. Behaviour of animals co-injected with NST (1 pmol) or NST-C6 (0.1 pmol) plus N/OFQ (10 pmol) was indistinguishable from that of controls. 6. These results reveal potent anxiogenic-like actions of NST and NST-C6, and confirm the anxiolytic-like properties of N/OFQ. As NST and N/OFQ both derive from preproN/OF, anxiety may be modulated in opposing directions depending on how this precursor is processed.