Authors: Qiu G et al.
Anesthesiology, January 26, 2026, 10.1097/ALN.0000000000005953
Summary
This mechanistic review and experimental synthesis explores whether impaired presynaptic neurotransmission represents a critical bottleneck to recovery from general anesthesia (GA), particularly with agents such as propofol and dexmedetomidine. While much of anesthetic pharmacology has historically focused on postsynaptic receptor modulation, growing evidence suggests that presynaptic machinery—specifically SNARE-complex–mediated vesicle release—plays a central role in both anesthetic-induced unconsciousness and delayed emergence.
Experimental data demonstrate that propofol selectively reduces syntaxin1A mobility within presynaptic membranes while leaving synaptobrevin mobility unaffected, indicating that anesthetic interference likely occurs before vesicle fusion rather than after exocytosis. The abolishment of propofol’s immobilizing effects on syntaxin1A when SNAP25 is disabled (eg, by botulinum neurotoxins) implicates SNAP25 as a key molecular target in anesthetic action. These findings support a model in which GA molecules bind to lipophilic pockets exposed during a partially zipped SNARE complex, increasing the energetic barrier for vesicle fusion beyond what calcium-triggered synaptotagmin activation can overcome.
Importantly, this presynaptic disruption may differentially affect neuronal populations depending on SNARE isoform expression. Some inhibitory synapses utilize alternative SNAP proteins (eg, SNAP23), potentially explaining variability in anesthetic sensitivity across neuronal subtypes and circuits. This molecular heterogeneity may contribute to differences in induction, maintenance, and emergence profiles observed clinically.
The review also addresses why clinical evidence for presynaptic anesthetic mechanisms has been limited. Core synaptic release proteins are highly conserved, and disruptive mutations are often lethal, reducing observable human phenotypic variation. Nevertheless, emerging genomic data show an association between SNAP25 polymorphisms and recovery time following propofol anesthesia in humans, supporting the concept that presynaptic mechanisms influence recovery inertia independent of surgical factors.
The authors propose that recovery from GA is slower and more complex than induction because presynaptic processes—such as neurotransmitter recycling, vesicle transport, mitochondrial ATP production, and cargo trafficking—are metabolically intensive and require coordinated restoration. In contrast, synaptic release is typically primed, making presynaptic SNARE interference an acute and potent mechanism for anesthetic induction and maintenance.
Future directions emphasize hypothesis-driven discovery of anesthesia reversal agents targeting specific presynaptic processes. Reductionist models using cultured neurons may allow systematic screening of candidate compounds capable of restoring baseline neurotransmission. The authors note that reversal may require multiple agents addressing distinct presynaptic targets rather than a single universal antidote. Intriguingly, nonanesthetic analogs of propofol have already demonstrated the ability to reverse anesthetic behavioral effects in animal models, suggesting recovery pathways may be mechanistically separable from sedation itself.
Key Points
• General anesthetics impair presynaptic neurotransmission by interfering with SNARE-complex dynamics rather than solely acting on postsynaptic receptors
• Propofol selectively alters syntaxin1A and SNAP25 function, implicating vesicle priming as a critical anesthetic target
• Presynaptic mechanisms may represent a major bottleneck to anesthetic recovery and emergence inertia
• Genetic variation in SNAP25 is associated with differences in recovery time in humans
• Targeting presynaptic processes may enable the development of anesthesia reversal or recovery-enhancing agents
Thank you to Anesthesiology for allowing us to summarize and discuss this important contribution advancing our understanding of anesthesia recovery mechanisms.