Nociceptin/Orphanin FQ Increases Anxiety-Related Behavior and Circulating Levels of Corticosterone During Neophobic Tests of Anxiety
Nociceptin/orphanin FQ (NC) modulates spontaneous locomotor activity (LA) in mice. NC applied intracerebroventricularly (i.c.v.) has been reported to stimulate LA at low doses (0.001–0.01 nmol) while inhibiting LA at higher doses (1–10 nmol). In the present study, the effects of NC on LA in mice were evaluated and the receptor involved characterized using NC receptor (OP4) agonists and antagonists. No significant differences were found in the LA (30-min observation period) between non-injected mice, mice injected with saline (2 µl/mouse, i.c.v.), or with low doses of NC (0.001 nmol and 0.01 nmol). In the 0.1–10 nmol range, NC caused a dose-dependent, naloxone-insensitive reduction of LA. The effects of the natural peptide were mimicked by NCNH2 and NC(1–13)NH2 while shorter fragments were inactive (NC(1–12)NH2, NC(1–9)NH2). [Phe1ψ(CH2-NH)Gly2]NC(1–13)NH2 ([F/G]NC(1–13)NH2) was inactive at 0.1 nmol and 1 nmol, while causing a partial reduction of LA at 10 nmol. One nmol of the pseudopeptide also prevented the inhibitory effect of 1 nmol NC. Ten nmol [Nphe1]NC(1–13)NH2 did not modify LA per se, but fully prevented the inhibitory action of 1 nmol NC. Results indicate that [F/G]NC(1–13)NH2 and [Nphe1]NC(1–13)NH2 behave as a partial agonist and a pure antagonist of OP4 sites, respectively. Taken together, these data demonstrate that NC inhibits LA in mice by activating OP4 receptor sites.