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

Abstract

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 e ect 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 e ects at 0.1 pmol. 4 N/OFQ (1 ± 100 pmol) increased percentages of entries into (control 38.5+3.4%; peak e ect 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 E ects 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 con®rm 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.

Nociceptin/Orphanin FQ Increases Anxiety-Related Behavior and Circulating Levels of Corticosterone During Neophobic Tests of Anxiety

“…The contradiction between the anxiogenic behavioral actions of N/OFQ in the present neophobic tests and the anxiolytic actions in similar previous neophobic tests (Jenck et al, 1997;Gavioli et al, 2002) is particularly puzzling. There were no obvious differences in effective doses across the various neophobic tests in these studies.…”

“…administration of N/OFQ (0.001-1.0 nmole) increases the expression of anxiety-related behaviors and plasma concentrations of CORT in rats during exposure to the three neophobic tests of anxiety. The behavioral findings conflict with previous reports that N/OFQ and an N/OFQ analogue (Ro64-6198) are anxiolytic in a variety of assays (Jenck et al, 1997(Jenck et al, , 2000Griebel et al, 1999;Wichmann et al, 2000;Dautzenberg et al, 2001;Gavioli et al, 2002). The reasons for these contradictory results are discussed.…”

“…In previous reports, it has been described that administration of N/OFQ (Jenck et al, 1997;Griebel et al, 1999;Gavioli et al, 2002) or the synthetic N/OFQ analogue Ro 64-6198 (Jenck et al, 2000;Wichmann et al, 2000;Dautzenberg et al, 2001) decreased fear-and anxiety-related behaviors in a variety of assays. In fact, when we initially reported that N/OFQ increases circulating ACTH and CORT concentrations in unstressed and mildly stressed rats (Devine et al, 2001), we reconciled our hormonal findings with the published behavioral data (Jenck et al, 1997;Griebel et al, 1999) on the basis that a variety of drugs that are anxiolytic can also increase circulating CORT concentrations in unstressed or mildly stressed rats (Ellis, 1966;Kakihana et al, 1968;Marc and Morselli, 1969;Tabakoff et al, 1978;Rivier et al, 1984;Matheson et al, 1988Matheson et al, , 1997ade Boer et al, 1991).…”

“…In one of the previous studies (Gavioli et al, 2002), the N/OFQ-treated rats spent approximately 75% of the test session on the open arms of the elevated plus maze. This preference for the open arms suggests that something other than anxiety state affected the behavior of the mice.…”

“…In one study, the doses were in the range of 10 pmoles-0.1 nmole i.c.v. in 2.0 ml phosphate buffered saline in mice (Gavioli et al, 2002). In another, the doses were 30 pmoles-3.0 nmoles i.c.v.…”