Orexin receptor antagonists attenuate acute stress-induced disruptions in sleep states

Post-traumatic stress disorder (PTSD) is characterized by symptoms including hypervigilance, intrusive memories, and sleep disturbance. Insomnia and nightmares are among the most common and clinically important sleep-related symptoms in PTSD, yet effective and well-tolerated pharmacotherapies remain limited. Suvorexant, a dual orexin receptor antagonist (DORA) approved for insomnia, represents a mechanistically distinct approach to traditional hypnotics. The orexin/hypocretin system is composed of two wake-promoting neuropeptides, orexin A and orexin B, which signal through orexin 1 (OX₁R) and orexin 2 receptors (OX₂R) to regulate arousal and sleep-wake transitions. The adaptive stress response, which is canonically disrupted in PTSD, is also moderated by the orexin system. Here, we used an acute inescapable footshock paradigm to disrupt sleep in adult male Sprague Dawley rats and evaluated whether orexin receptor antagonism restores sleep after stress. Systemic administration of a dual orexin receptor antagonist (suvorexant), an OX₁R-preferring antagonist (SB334867), and an OX₂R-selective antagonist (EMPA), partially restored REM sleep and attenuated increases in NREM sleep following footshock stress exposure. We also examined the relative contribution of OX₁R and OX₂R to these effects at the doses used. Although all antagonists increased time spent in REM after footshock stress, attenuation of the stress-induced increases in NREM and reductions in sleep-onset latency were most evident following dual receptor blockade. These findings demonstrate that orexin receptor antagonism can mitigate acute stress-induced alterations in sleep state allocation and sleep latency, and support further investigation of DORAs for stress-related sleep disturbance.