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.
Why It Matters
This mechanistic study delineates a specific striatal circuit and receptor mechanism by which orexin modulates emergence from anesthesia, advancing our understanding of consciousness control under anesthesia.
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.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic experimental study in rodents; not clinical evidence.
- Study Design
- OTHER