Sleep-promoting effects of preproorexin C-terminal peptide in mice

The hypothalamic orexin system plays an essential role in the stabilization of sleep and wakefulness. Orexin A and orexin B, a pair of neuropeptides derived from a common precursor protein, preproorexin, promote wakefulness. However, the functional role of preproorexin C-terminal peptide (OXC) remains unknown. In the present study, we investigated the pharmacological effects of a synthetic mouse OXC on sleep and wakefulness in C57BL/6J mice. The intracerebroventricular administration of OXC (0.3-3 nmol/mouse) at the beginning of the dark/active phase reduced the total time spent in wakefulness and increased the total time spent in non-rapid eye movement (NREM) sleep in a dose-dependent manner. A slight increase in rapid eye movement (REM) sleep was also observed. In addition to the increase in sleep quantity, OXC increased the duration of NREM and REM sleep episodes, a marker of sleep quality. Mice in which sleep was promoted by OXC showed decreases in locomotor activity and food intake. The reversed form of mouse OXC, a negative control substance, had no effect on sleep or wakefulness in mice. When orexin A and OXC were co-administered at the same doses, orexin A (0.3 nmol) promoted wakefulness in the presence of OXC (0.3 nmol), whereas OXC (1 nmol) promoted sleep in the presence of OXA (1 nmol). These results suggest that as the dose of OXC increases, it counteracts the wake-promoting effects of orexin A. Therefore, the present study identified OXC as a novel sleep-promoting substance in mice.