Effects of nociceptin on the exploratory behavior of mice in the hole-board test.

The effects of nociceptin on the exploratory behavior of mice were examined using an automatic hole-board apparatus. A low dose of nociceptin (0.01 nmol, i.c.v.) had an anxiolytic effect, as reflected by an increase in head-dipping behavior. However, high doses of nociceptin (1-5 nmol, i.c.v.) produced a dose-dependent anxiogenic effect, as reflected by a decrease in head-dipping behavior. Both the anxiolytic and anxiogenic effects of nociceptin were antagonized by nocistatin, an opioid receptor-like 1 (ORL1) receptor antagonist. Although a low dose (0.01 nmol, i.c.v.) of nociceptin significantly increased the rate of serotonin (5-hyroxytryptamine, 5-HT) turnover in the hippocampus, a high dose (5 nmol, i.c.v.) of nociceptin significantly decreased this turnover in the amygdala. Furthermore, the anxiolytic effect of nociceptin at a low dose was antagonized by N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide 3HCl (WAY100635), a 5-HT1A receptor antagonist. On the other hand, the anxiogenic effect of nociceptin at a high dose was antagonized by R(+)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT), a 5-HT1A receptor agonist. In conclusion, the results of this study suggest that nociceptin has dose-related anxiolytic and anxiogenic effects as a result of the activation of ORL1 receptors. The present results also suggest that a low dose of nociceptin has an anxiolytic effect via the activation of 5-HT ergic function in the hippocampus, while a high dose of nociceptin has an anxiogenic effect via the inhibition of 5-HT ergic function in the amygdala.