Sevoflurane is a widely used inhaled general anesthetic, administered to patients for various surgical procedures. It reliably induces a state characterized by unconsciousness, a lack of memory, and immobility in response to surgical stimulation. While its widespread use is clear, the precise way sevoflurane achieves these effects is complex, involving interactions with multiple molecular targets throughout the central nervous system.
The Shift from Lipid to Protein Theories
Early investigations into how anesthetics work centered on the Meyer-Overton hypothesis, which observed a correlation between an anesthetic’s potency and its solubility in olive oil. This observation led to the idea that anesthetics might exert their effects by dissolving into and altering the properties of the lipid components of cell membranes. The theory suggested that once a certain concentration was reached within the lipid layer, anesthetic effects would manifest.
However, this lipid-based theory faced challenges that revealed its incompleteness. For instance, stereoisomers, which possess identical lipid solubilities, can exhibit vastly different anesthetic potencies. Some long-chain compounds, despite high lipid solubility, demonstrate no anesthetic effect, a phenomenon known as the “cutoff effect.” These exceptions highlighted that anesthetic action was likely more specific than a simple dissolution into cellular lipids.
Modern understanding has shifted to the protein theory of anesthesia. This suggests that anesthetics like sevoflurane achieve their effects by directly binding to specific sites on proteins, particularly various ion channels embedded within neuronal membranes. This direct interaction with proteins allows for more selective and nuanced modulation of neuronal activity, providing a more comprehensive explanation for the diverse effects observed during anesthesia.
Enhancing Inhibitory Neurotransmission
Sevoflurane enhances the “off” signals within the nervous system, contributing to the depression of brain activity during anesthesia. A primary target for this action is the gamma-aminobutyric acid type A (GABA-A) receptor, which is the main inhibitory neurotransmitter receptor in the brain. Sevoflurane potentiates the effect of GABA, leading to an increased flow of chloride ions into neurons.
This influx of negatively charged chloride ions causes the neuron’s membrane potential to become more negative, a process called hyperpolarization. A hyperpolarized neuron is less excitable and less likely to generate an electrical signal, effectively dampening neuronal activity. This mechanism is a major contributor to the sedative, hypnotic, and anxiolytic effects observed with sevoflurane, including the induction of unconsciousness by depressing neurons in specific regions like the medial parabrachial nucleus.
Beyond GABA-A receptors, sevoflurane also activates two-pore domain potassium (K2P) channels, which are responsible for background potassium currents. When activated by sevoflurane, these channels allow potassium ions to exit the neuron. This outflow of positively charged potassium ions further contributes to neuronal hyperpolarization, thereby reducing overall neuronal excitability and promoting widespread neuronal depression.
Sevoflurane also influences glycine receptors, which are another type of inhibitory neurotransmitter receptor, particularly abundant in the spinal cord. Like GABA-A receptors, glycine receptors mediate inhibitory signals. By potentiating the activity of glycine receptors, sevoflurane further contributes to the overall inhibitory state of the central nervous system, playing a role in the immobility component of general anesthesia.
Reducing Excitatory Neurotransmission
In addition to amplifying inhibitory signals, sevoflurane simultaneously reduces “on” signals, further contributing to the anesthetic state. A significant mechanism involves the inhibition of N-methyl-D-aspartate (NMDA) receptors. These receptors are typically activated by glutamate, the brain’s primary excitatory neurotransmitter, and play a role in synaptic plasticity and memory formation.
By inhibiting NMDA receptor function, sevoflurane reduces overall neuronal excitability, a factor in its anesthetic and amnesic properties. This action contributes to the patient’s loss of awareness and memory during surgery.
Sevoflurane also exerts inhibitory effects on nicotinic acetylcholine (nACh) receptors. These receptors are found in various excitable tissues, including the brain and muscle, where they mediate rapid signal transmission. Sevoflurane’s interaction with nACh receptors dampens excitatory neurotransmission.
Sevoflurane modulates voltage-gated sodium channels (NaV channels), which are responsible for generating and propagating electrical signals in neurons. Inhibition of these presynaptic NaV channels, particularly in the spinal cord, can reduce the release of neurotransmitters. This contributes to the immobility aspect of general anesthesia by disrupting the transmission of motor commands.
Integrated Effects on the Central Nervous System
The observable state of general anesthesia induced by sevoflurane arises from the integrated effects of its molecular actions across different regions of the central nervous system. The potentiation of GABA-A receptors and activation of K2P channels in areas such as the cerebral cortex, thalamus, and brainstem are fundamental to inducing unconsciousness. These actions disrupt the normal patterns of brain activity, leading to changes in electroencephalogram (EEG) signals.
This widespread neuronal inhibition also leads to a disruption of functional connectivity within key brain networks that are active during wakefulness. The weakening of these neural connections contributes to the patient’s loss of awareness and responsiveness.
Amnesia, the lack of memory formation during anesthesia, is significantly influenced by sevoflurane’s inhibition of NMDA receptors, particularly within the hippocampus. This brain region is widely recognized for its central role in the processes of memory consolidation and retrieval. By interfering with NMDA receptor function, sevoflurane effectively prevents the brain from forming new memories of the surgical experience.
The immobility achieved during sevoflurane anesthesia is primarily mediated by its actions in the spinal cord. This includes the potentiation of glycine receptors, which enhance inhibitory signals in motor pathways. Additionally, the modulation of voltage-gated sodium channels in the spinal cord contributes to muscle relaxation and the prevention of movement in response to surgical stimuli. The multifaceted actions of sevoflurane, occurring simultaneously across various brain and spinal cord regions, converge to produce the comprehensive state of general anesthesia.