In a recent issue of Anesthesiology, John and Prichep1outlined a neurophysiologic theory of anesthesia. According to this theory, loss of awareness and amnesia are produced in six steps. In steps 1 and 2, depression of the brainstem reticular activation system causes diminution of availability of acetylcholine, resulting in decreased reactivity of the limbic system and block of memory storage. In steps 3 and 4, further depression of the reticular activation system results in closure of thalamic gates, thereby blocking reverberations in the thalamocortical system. Finally, in steps 5 and 6, parietal–frontal transactions are blocked, prefrontal cortex is depressed, and unconsciousness occurs.

After this sequence of events, brainstem cholinergic neurons should be significantly depressed at subhypnotic and hypnotic anesthetic concentrations (steps 1 and 2), leading to decreased cholinergic activation of the thalamocortical system. However, studies on the effects of anesthetics on neurons in brainstem cholinergic nuclei report a moderate (approximately 20%) decrease in activity at anesthetic concentrations twofold higher than those producing sedation and amnesia.2Furthermore, blockers of brain acetylcholine receptors should be potent hypnotics, if decreased cholinergic activation of the thalamocortical system is a central mechanism of anesthetic action. However, this is clearly not the case. Clinically used hypnotics such as propofol and etomidate do not induce unconsciousness via  blocking acetylcholine receptors.3Taken together, the authors’ statement that anesthetic-induced sedation and amnesia are causally related to a decreased concentration of acetylcholine in the brain is not backed by experimental evidence.

In steps 3 and 4, it is assumed that further depression of the reticular activation system is resulting in closure of thalamic gates. Unlike most other anesthetics, etomidate and ketamine do not attenuate thalamic information transfer in the somatosensory system when applied at hypnotic concentrations.4,5Obviously, depression of thalamic gating is not a necessary requirement for producing unconsciousness, as assumed by an “anesthetic cascade.” In addition, it is difficult to follow John and Prichep’s implicit assumption that different anesthetic agents produce unconsciousness via  the same neurophysiologic mechanism. This issue clearly needs careful elucidation.

In the last step of the model, it is proposed that prefrontal cortex is depressed to reduce awareness: The anesthetic cascade explains unconsciousness by a bottom-up approach: The starting point is in the brainstem. At higher concentrations, the prefrontal cortex gets involved. However, experimental data available so far seem to be better explained by a top-down approach. There is considerable evidence that cortical neurons are more sensitive to anesthetic treatment compared with neurons in the brainstem.3,6 

How might anesthetic agents work? Ion channels, highly sensitive to general anesthetics, exist in almost all parts of the central nervous system, including the neocortex, hippocampus, amygdala, thalamus, and spinal cord.7,8There is increasing evidence that the amnestic, sedative, and hypnotic properties of anesthetic agents are mediated by molecular targets located in diverse neural networks. For example, studies in knockout mice showed that a specific γ-aminobutyric acid type A receptor subtype, most prominently expressed in the hippocampus, is involved in learning and memory.9This receptor is significantly modulated by very small concentrations of isoflurane.10Therefore, molecular targets located in hippocampal pyramidal cells most probably contribute to the amnestic properties of isoflurane.

What about anesthetic-induced sedation? Benzodiazepines and intravenous anesthetics produce sedation via γ-aminobutyric acid receptors, present in the cerebral cortex in high densities.11,12There is a linear relation between the reduction in metabolic blood flow that occurs during propofol-induced hypnosis and the known regional benzodiazepine binding sites, suggesting that cortical γ-aminobutyric acid receptors mediate anesthetic-induced depression of cortical networks in humans.13A similar conclusion has been drawn from animal studies. Recent investigations showed that neocortex is a major substrate of sedative and hypnotic concentrations of volatile anesthetics.6The presence or absence of brainstem cholinergic nuclei had no influence on the depressive effects of volatile anesthetics on spontaneous firing of cortical neurons. Similarly, anesthetic-induced alterations of rhythmic brain activity, in particular attenuation of γ oscillations or induction of θ/δ oscillations have been observed in isolated cortical circuits, in the absence of subcortical structures.14,15All of these data indicate that sedation, and in part hypnosis, are largely mediated by molecular targets located in the cerebral cortex.

With the above arguments, I do not intend to state that brainstem cholinergic nuclei and sleep pathways are irrelevant in the context of anesthesia. They probably come into play. Instead, my criticism addresses the theoretical concept: John and Prichep’s theory is a unitary theory of anesthetic action. The authors do not assume that a single ion channel causes amnesia and hypnosis, but they assume that a single neural substrate does it. Approximately 10 yr ago, Kendig,16Eger et al. ,17and Kissing18proposed a different theory. They argued that anesthetics produce different aspects of anesthesia at different sites in the central nervous system by different molecular targets. That is, anesthesia is composed of elementary components, largely independent on each other. This “old” idea is in line with many recent findings. For example, the sedative and hypnotic actions of intravenous anesthetics can be distinguished by the subtype of γ-aminobutyric acid receptor that is involved.19,20For example, amnesia and sedation are distinct components of anesthetic action that can be separated experimentally.21All of these observations argue against a unitary brain mechanism producing the diverse aspects of anesthetic action in the central nervous system. They argue against something like an anesthetic cascade as well.

University of Tuebingen, Tuebingen, Germany.

John ER, Prichep LS: The anesthetic cascade: A theory of how anesthesia suppresses consciousness. Anesthesiology 2005; 102:447–71
Ogawa T, Shingu K, Shibata M, Osawa M, Mori K: The divergent actions of volatile anaesthetics on background neuronal activity and reactive capability in the central nervous system. Can J Anesth 1992; 39:862–72
Rudolph U, Antkowiak B: Molecular and neuronal substrates for general anaesthetics. Nature Rev Neurosci 2004; 5:709–20
Angel A, Arnott RH: The effect of etomidate on sensory transmission in the dorsal column pathway in the urethane-anaesthetized rat. Eur J Neurosci 1999; 11:2497–505
Schubert A, Licina M, Lineberry PJ: The effect of ketamine on human somatosensory evoked potentials and its modification by nitrous oxide. Anesthesiology 1990; 72:33–9
Hentschke H, Schwarz C, Antkowiak B: Neocortex is the major target of sedative concentrations of volatile anaesthetics: strong depression of firing rates and increase of GABAA receptor-mediated inhibition. Eur J Neurosci 2005; 21:93–102
Campagna JA, Miller KW, Forman SA: Mechanisms of actions of inhaled anesthetics. N Engl J Med 2003; 348:2110–24
Urban BW: Current assessment of targets and theories of anaesthesia. Br J Anaesth 2002; 89:165–83
Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Otu FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Whiting PJ, Rosahl TW: Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 2002; 22:5572–80
Caraiscos VB, Newell JG, You T, Elliott EM, Rosahl TW, Wafford KA, MacDonald JF, Orser BA: Selective enhancement of tonic GABAergic inhibition in murine hippocampal neurons by low concentrations of the volatile anesthetic isoflurane. J Neurosci 2004; 24:8454–8
Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Mohler H: Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 1999; 401:796–800
Möhler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002; 300:2–8
Alkire MT, Haier RJ: Correlating in vivo anaesthetic effects with ex vivo receptor density data supports a GABAergic mechanism of action for propofol, but not for isoflurane. Br J Anaesth 2001; 86:618–26
Dickinson R, Awaiz S, Whittington MA, Lieb WR, Franks NP: The effects of general anaesthetics on carbachol-evoked gamma oscillations in the rat hippocampus in vitro. Neuropharmacology 2003; 44:864–72
Drexler B, Roether CL, Jurd R, Rudolph U, Antkowiak B: Opposing actions of etomidate on cortical theta oscillations are mediated by different γ-aminobutyric acid type A receptor subtypes. Anesthesiology 2005; 102:346–52
Kendig JJ: Spinal cord as a site of anesthetic action. Anesthesiology 1993; 79:1161–2
Eger II, EI Koblin, DD, Harris RA, Kendig JJ, Pohorille A, Halsey MJ, Trudell JR: Hypothesis: Inhaled anesthetics produce immobility and amnesia by different mechanisms at different sites. Anesth Analg 1997; 84:915–8
Kissin I: A concept for assessing interactions of general anesthetics. Anesth Analg 1997; 85:204–10
Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F, Zaugg M, Vogt KE, Ledermann B, Antkowiak B, Rudolph U: General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta 3 subunit. FASEB J 2003; 17:250–2
Reynolds DS, Rosahl TW, Cirone J, O’Meara, GF, Haythornthwaite A, Newman RJ, Myers J, Sur C, Howell O, Rutter AR, Atack J, Macaulay AJ, Hadingham KL, Hutson PH, Belelli D, Lambert JJ, Dawson GR, McKernan R, Whiting PJ, Wafford KA: Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms. J Neurosci 2003; 23:8608–17
Veselis RA, Reinsel RA, Feshchenko VA: Drug-induced amnesia is a separate phenomenon from sedation: Electrophysiologic evidence. Anesthesiology 2001; 95:896–907