Characterization of the locomotor activity-inhibiting effect of noeiceptin/orphanin FQ in mice

Nociceptin/orphanin FQ (NC) modulates spontaneous locomotor activity (LA) i n 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 d oses (1-10 nmol). In the present study, the effects of NC on LA in mice were evaluated and th e receptor involved characterized using NC receptor (OP4) agonists and anta gonists. No significant differences were found in the LA (30-min observatio n period) between non-injected mice, mice injected with saline (2 mul/mouse , i.c.v.), or with low doses of NC (0.001 nmol and 0.01 nmol). In the 0.1-1 0 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). [Phe(1 )psi (CH2-NH>Gly(2)]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 o f the pseudopeptide also prevented the inhibitory effect of 1 nmo1 NC. Ten nmol [Nphe(1)]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)NH, and [Nphe(1)]NC(1-13)NH2 behave as a partial agonist and a pure antagonist of OP4 sites, respectively. Taken together, these data demonstrate that NC inh ibits LA in mice by activating OP4 receptor sites.