Awakening Recovery: Enhancing Orexinergic Tone After Acute CNS Damage

Acute injuries to the central nervous system (CNS) share a rapid disruption of arousal, autonomic stability, and neuroimmune balance. Among the neuromodulatory systems affected, the orexin (hypocretin) network is uniquely positioned at the intersection of wakefulness, autonomic control, and motivated behavior. Experimental evidence across ischemic, hemorrhagic, traumatic, and systemic models shows that orexin signaling is sharply suppressed during the early post-injury collapse and gradually recovers as arousal circuits and homeostatic functions stabilize. Controlled enhancement of orexinergic tone has been found to improve arousal state, modulate inflammatory responses, and support behavioral engagement, although these effects are highly dependent on timing, receptor subtype, and physiological context. This review synthesizes evidence from ischemia, hemorrhagic stroke, traumatic brain and spinal cord injury, and systemic inflammatory states, and examines the conceptual and translational rationale for targeting orexin pathways. We summarize available pharmacological, peptide-based, neuromodulatory, and physiological strategies to boost orexinergic tone, highlighting the growing development of selective OX2 agonists and experimental approaches to enhance endogenous orexin activity. By integrating findings across etiologies within a timing-aware framework, this review addresses a gap in the current literature, which has largely treated these injuries in isolation. While clinical testing in acute CNS injury has not yet been performed, the mechanistic convergence across etiologies suggests that orexinergic modulation may offer a phase-sensitive means to stabilize arousal and support recovery. Taken together, orexin emerges as a state-dependent integrator whose modulation could complement existing therapies by linking early arousal stabilization with longer-term motivational and functional recovery.