Orexin signalling in the nucleus accumbens promotes arousal from isoflurane anaesthesia and restores communication between the nucleus accumbens and frontal cortex.

Summary

In mice, orexinergic inputs to the nucleus accumbens are wake-active during isoflurane anesthesia and arousal. Optogenetic activation of NAc orexin terminals reduced burst suppression, delayed induction, accelerated emergence, and orexin-A microinjection promoted arousal; effects involved OX1R on D1R-positive neurons and restored NAc–frontal cortex communication.

Key Findings

• Orexinergic afferents in NAc are wake-active during isoflurane anesthesia and arousal.
• Optogenetic activation of NAc orexin terminals reduced burst suppression ratio from 67.4% to 14.5% at 1.4 vol% isoflurane (n=6, P<0.001), delayed induction, and shortened emergence.
• NAc microinjection of orexin-A promoted arousal; OX1R predominantly on D1R-positive neurons mediated effects and restored NAc–frontal cortex communication.

Clinical Implications

Targeting orexin–NAc pathways or OX1R on D1R-positive neurons could inspire pharmacologic strategies to hasten emergence or mitigate EEG burst suppression, pending translational safety and efficacy data.

Limitations

• Preclinical rodent model; human translatability and safety are unknown
• Findings are specific to isoflurane and may not generalize across anesthetic agents

Future Directions

Test orexinergic modulators in large-animal models and early-phase clinical trials to evaluate emergence profiles, EEG dynamics, cognition, and safety; assess agent-specific generalizability.