Current models of insomnia disorder: a theoretical review on the potential role of the orexinergic pathway with implications for insomnia treatment.

Insomnia disorder is considered as a stress-related disorder associated with hyperarousal, stress and emotion dysregulation and the instability of the 'flip-flop' switch system. The orexinergic system is well known for its key role in sleep and arousal processes but also in the allostatic system regulating stress and emotions and may thus be of major interest for insomnia and its treatment. Accordingly, we discuss the potential role of orexins on sleep processes, brain systems modulating stress and emotions with potential implications for insomnia pathophysiology. We reviewed available data on the effect of dual orexin receptor antagonists (DORAs) on sleep and brain systems modulating stress/emotions with implications for insomnia treatment. We present our findings as a narrative review. Few data in animals and humans have reported that disrupted sleep and insomnia may be related to the overactivation of orexinergic system, while some more consistent data in humans and animals reported the overactivation of orexins in response to acute stress and in stress-related disorders. Taken together these findings may let us hypothesise that an orexins overactivation may be associated with stress-related hyperarousal and the hyperactivation of arousal-promoting systems in insomnia. On the other hand, it is possible that by rebalancing orexins with DORAs we may regulate both sleep and allostatic systems, in turn, contributing to a 'switch off' of hyperarousal in insomnia. Nevertheless, more studies are needed to clarify the role of the orexin system in insomnia and to evaluate the effects of DORAs on sleep, stress and emotions regulating systems.