Multimodal anesthesia and systems neuroscience: the new frontier.

MECHANISTIC research is entering an exciting era in which knowledge about the molecular targets for general anesthetics is beginning to influence clinical practice. Identifying the receptors and neuronal circuits that underlie the neurobehavioral effects of anesthetics is particularly important if we are to develop new anesthetic agents and advance beyond the “ether era.” The clinical properties of contemporary inhaled anesthetics are considerably more desirable than ether; nevertheless, these halogenated hydrocarbons have an extraordinarily low therapeutic index and cause widespread neurodepression. The anesthetic state encompasses several behavioral endpoints, including loss of consciousness, amnesia, immobility, and analgesia. The current clinical practice of “balanced anesthesia” depends on a combination of drugs that are relatively nonselective to produce these behavioral endpoints. A popular working hypothesis is that the next generation of general anesthetics will be based on a multimodal strategy, whereby patients will receive drugs that target highly specific receptor populations and neuronal networks to produce the desired behaviors. In this context, the article by Vanini et al. is important because it identifies a region of the brain stem that contributes to the loss of consciousness produced by the anesthetic isoflurane. The authors used microdialysis to measure levels of -aminobutyric acid (GABA) in the pontine reticular formation of cats, during wakefulness and isoflurane anesthesia. GABA levels decreased during anesthesia, and the power of the electroencephalogram and activity of the electromyogram covaried with the GABA levels. They also found that injection of a GABA reuptake inhibitor, nipecotic acid, into the pontine reticular formation of rats increased isoflurane induction time, whereas injection of a GABA synthesis inhibitor, 3-mercaptopropionic acid, had the opposite effect. From these results, they conclude that isoflurane anesthesia is due, at least in part, to a decrease of GABA levels in the pontine reticular formation. The authors are to be commended because, despite the accumulation of much information over the past several decades about anesthetic-sensitive receptors, few researchers have attempted to situate this information in the context of how the central nervous system operates at the systems level. Systems neuroscience is the field of science research that studies the function of neuronal circuits and connectivity relations between neuronal networks with in vivo models in intact subjects. It has been proposed that a systems approach is essential for contemporary drug discovery and development. Nevertheless, only recently have attempts been made to determine which neuronal networks are augmented or depressed, the anesthetic dosages at which these effects occur, and how such effects result in behavioral phenomena. 6 To achieve the goal of multimodal anesthesia, we must identify, at the systems neuroscience level, the anesthetic actions that are necessary and sufficient to produce the desired behavioral end points. This task is extraordinarily challenging because of the complexity of human neurophysiology and anesthetic pharmacology. Although such complexity is daunting, it can be exploited for therapeutic gain. To appreciate the level of complexity and illustrate why we need to understand network relations and connectivity, let us consider the effects that anesthetics have on a single neurotransmitter system. GABA is the major inhibitory transmitter in the central nervous system. The GABAA subtype of receptor is a chloridepermeable ion channel that mediates the majority of GABAergic actions. GABAA receptors are ubiquitous in the central nervous system, and most general anesthetics increase their activity, causing an increase in membrane permeability to chloride and an influx of negatively charged ions. This results in membrane hyperpolarization, the shunting of excitatory input, and depression of neuronal firing. Most inhaled and injectable anesthetics have at least three distinct concentration-dependent actions on GABAA receptors: They increase the potency of endogenous GABA, they modify receptor desensitization, and they directly activate the channel in the absence of GABA. The GABAA receptor is a heteropentameric complex made up of subunits encoded by at least 19 genes. The subunit composition of the GABAA receptors dramatically alters the potency of GABA and the pharmacology of the receptors, most notably with regard to the effectiveness of general anesthetics. The distribution of subunits varies considerably between brain region, the neuronal population within a region, and even the subcellular domains of a single This Editorial View accompanies the following article: Vanini G, Watson CJ, Lydic R, Baghdoyan HA: -Aminobutyric acid– mediated neurotransmission in the pontine reticular formation modulates hypnosis, immobility, and breathing during isoflurane anesthesia. ANESTHESIOLOGY 2008; 109:978–88.