Ruolo dell'orexina nell'ansia e nei disturbi legati allo stress: studi preclinici e clinici

Orexin is a neuropeptide involved in the modulation of different physiological functions, including the circadian rhythm, appetite, but also mood. Therefore, it plays a critical role in neurodisorders such as narcolepsy, insomnia, addiction, depression and anxiety. Preclinical studies in adult mice were conducted to induce social stress by aggression from larger mice, thanks to the use of the Stress-Alternatives Model (SAM) experimental apparatus. This test induces the subjects to make a choice: remain in the arena (Stay phenotype) or exit through one of the two escape holes (Escape phenotype). The first group of mice showed higher anxiety levels, as expressed by the many reliable laboratory parameters analyzed, like freezing and startle response to a stimulus, time spent attentive to the escape hole, or corticosterone plasma concentration. It was demonstrated that a stimulation of the Orexin 2 receptor leads to a significant percentage of switch from the Stay phenotype to the Escape one, suggesting an anxiolytic effect, associated with the activation of a group of inhibitory GABAergic neurons in the amygdala. The same was confirmed through the Social Interaction/Preference (SIP) test. On the other hand, Orx 1 receptor stimulation leads to an anxiogenic profile via the activation of a group of glutamatergic neurons in the basolateral amygdala (BLA). Its antagonism, however, allows the switch from stress-sensitive to stress-resilient phenotype. These results together provide evidence for a receptor-driven mechanism that balances pro- and anti-stress responses within the BLA. However, more evidence was needed to extend the findings to humans. For this purpose, the No-Predictable-Unpredictable (NPU) paradigm was used in human volunteers and data showed that Suvorexant, a dual Orexin receptor antagonist, is able to revert the symptoms of anticipatory anxiety, as reported by questionnaires submitted to the participants. A second group received the placebo and was used as control. Startle eyeblink was also recorded, as an index of aversive reactivity. Further studies in humans are necessary to allow for a better translation of the results from preclinical to clinical studies, but nonetheless these findings represent a promising starting point for the regulation of neurological symptoms that appear as a consequence of a dysregulation of the Orexin/receptor system. ​