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

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. 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. 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 (NST‐C6; 0.01 – 10 pmol) closely mimicked these actions of NST, with peak effects at 0.1 pmol. 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. 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. 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. British Journal of Pharmacology (2002) 136, 764–772; doi:10.1038/sj.bjp.0704739