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A Hollywood thriller due out this yearcenters on a young man who awakens while undergoing open-heart surgery but isunable to move or cry out. The fi lm’s plot will undoubtedly take many more dramaticturns from there, but its early premise is, sadly, not entirely far-fetched. Episodesof intraoperative awareness while under general anesthesia are reported by one ortwo of every 1,000 patients. In reality, such incidents are usually brief and generallydo not involve pain or distress, but they do highlight one of several ways that eventhe newest generation of anesthetic drugs can sometimes leave much to be desired.Indeed, the medical specialty of anesthesiology has evolved into a sophisticated artform because scientifi c understanding of how anesthetic drugs actually work, andhow to make them better, has lagged behind most other areas of drug development.Many of the modern anesthetics, in fact, share structural properties and clinicaleffects with ether, whose application as an anesthetic was fi rst successfully demonstratedin public by Boston dentist William Morton in 1846. Since then, the use ofgeneral anesthesia has expanded to 40 million patients each year in North Americaalone. Yet advances in anesthetic care since Morton’s day have come largely from thedevelopment of complex drug delivery systems and strategies for managing anesthesia’sdangers and side effects.

Today's general anesthetics are the most potent depressors of nervous sys­tem activity used in medicine. They even affect regulation of breathing and heart function. As a result, the drugs have a fairly narrow margin of safety, which is the difference between the therapeutic dose and a dose that is toxic, even lethal. That is one reason why individuals whose lung or cardiovascular function is already unstable—such as trauma vic­tims undergoing emergency operations or patients in the midst of heart sur­gery—must receive a lighter than nor­mal dose of anesthesia, which could make them susceptible to brief aware­ness incidents, as in the movie. Although radical improvements in the care of people under general anes­thesia have laid the foundation for com­plicated procedures such as organ trans­plants and open-heart surgery, the pow­erful neurodepressive effects of these drugs make them more likely to causedeath during an operation than the sur­gical procedure itself. And because an­esthesia-related mortality has plateaued at a rate of approximately one patient in 13,000 for the past 15 years, it appears that anesthesiologists may have reached the limits of our ability to deliver these toxins safely. Moreover, severe side ef­fects—ranging from loss of airway con­trol to memory and cognitive problems after general anesthesia—may also stem from the broad yet poorly understood infl uence that current anesthetics exert on the central nervous system. Science should be able to do much better, and very recent research is begin­ning to reveal how it can. Pulling Out the Plugs all of today's general anesthetic drugs were developed empirically, which is to say, they were tested for their ability to produce the desirable effects that defi ne the anesthetized state. Anes-thesia's main components are sedation, unconsciousness (also sometimes called hypnosis), immobility, absence of pain (analgesia) and absence of memory for the anesthetized period (amnesia). By studying the mechanisms through which anesthetics achieve these end points, many groups, including my own at the University of Toronto, are begin­ning to tease those effects apart. Such studies are revealing that the activity of these potent drugs involves highly spe­cifi c interactions with subpopulations of nervous system cells to create each of the separate properties of anesthesia. Armed with this knowledge, we will be poised to fi nally move beyond the ether era and develop a new generation of highly specifi c drugs that can be used in combinations to deliver only the de­sired results without the dangers. As a bonus, this research is also yielding in­sights that can improve related therapies, such as sedatives and sleep aids, that

share some of anesthesia's mechanisms. Anesthetics fall into two main cate­gories based on whether they are deliv­ered by inhalation, such as isofl urane, or intravenously, such as propofol. These drugs may appear to induce a deep sleep, but the state produced by most modern general anesthetics is more of a pharma­cological coma. In a step toward clarify­ing the mechanisms underlying their effects, technologies such as magneticing anesthesia. One leading theory holds that it is simply the result of "cognitive unbinding"—a severing of communica­tion between the many brain regions that usually cooperate in higher cogni­tive processing. Even at the local level, if one imagines groups of neurons as form­ing lines in a vast telephone network, the effect of general anesthesia is analogous to pulling out plugs at the switchboard. Researchers are, however, making en-contain subtly different versions, how­ever, which tend to predominate in dif­ferent areas of the central nervous sys­tem. The presence of particular receptor subtypes on only certain subpopulations of cells will thus determine which cells are infl uenced by an anesthetic. Contemporary studies are therefore focusing on identifying which receptor variants are the targets of current anes­thetic drugs, understanding how the
he effect of anesthesia is analogous to pulling out plugs at the switchboard.
resonance imaging (MRI) and positron-emission tomography (PET) have helped identify some of the discrete brain re­gions and neural circuits involved in spe­cific components of the anesthetized state. For instance, anesthetic action on the spinal cord accounts for the immobil­ity produced by the drugs, whereas drug-induced changes to the hippocampus, a brain structure involved in memory for­mation, have been linked to amnesia. Chronic memory impairment following surgery, one of the undesirable side ef­fects suffered by some patients, may also represent a leftover infl uence of the drugs on the hippocampus. Because consciousness is a complex experience whose defi ning properties are still hotly debated by neuroscientists, it is not as easy to pinpoint a single ana­tomical source of unconsciousness dur-couraging progress in discovering de­tails about the ways that anesthetic drugs physically act on the individual cells of the nervous system to block their transmissions. During most of the 20th century, an­esthetics were widely thought to work by disrupting the lipid components of cell membranes. Most anesthetics are highly fat-soluble compounds with widely dif­fering chemical structures that range from simple inert gases to complex ste­roids. Their great physical and chemical diversity supported the idea that anes­thetics must work in some nonspecifi c way to depress neuronal functioning. Modern research has shown, however, that anesthetics actually interact with multiple varieties of specifi c proteins, known as receptors, found on the sur­face of nerve cells. Families of receptorsdrugs interact with the receptors to change the cell's function and how those cellular changes produce both the desired and unwanted "symptoms" of anesthesia. Signaling Silence many categories of receptor pro­teins are found on the surface of neu­rons, but those activated by natural neu-rotransmitter chemicals have garnered the most interest in anesthesia research because they critically regulate commu­nication along the neural "telephone lines." As their name implies, neuro-transmitter molecules transmit messag­es between neurons at points of contact called synapses. They do so by traveling from the so-called presynaptic neuron across a tiny gap to bind to receptors on the postsynaptic neuron's cell mem­brane. When enough neurotransmitter molecules trigger the appropriate recep­tors, the postsynaptic cell's membrane generates an electrical potential that travels down its length to the next neu­ron in its network. Glutamate, sero­tonin, norepinephrine and acetylcholine are just a few of the neurotransmitters widely studied for their role in promot­ing such signaling through out the cen­tral nervous system. In anesthesia research, however, an­other neurotransmitter called gamma-aminobutyric acid (GABA) has gained the most attention because of its ability Overview/Refi ning a Blunt Instrument u General anesthetics are powerful nervous system suppressors, but how the drugs produce their broad effects throughout the brain and body is poorly understood. ■ Investigation of anesthetics' underlying mechanisms is revealing that individual aspects of the anesthetized state are attributable to different sets of nerve cells, which are themselves distinguished by specifi c surface proteins that interact with the drugs. ■ New compounds designed to target just those proteins, and hence only specifi c cell types, could be combined to selectively produce the desirable effects of anesthetics—as well as sedatives, sleep aids and memory drugs— with fewer risks and side effects.
to block neural communication. GABA is an inhibitory neurotransmitter: it helps to maintain overall balance in the nervous system by dampening neurons' ability to respond to excitatory messag­es from other cells. For that reason, GABA is thought to play a central part in the actions of anesthetic drugs. Most postsynaptic receptors on cells that interact with GABA belong to a class termed ligand-gated ion channels. When GABA (the ligand) binds to the receptor, the receptor changes its con­formation, temporarily opening a chan­nel that admits negatively charged ions into the cell. The increased ion concen­tration generates a negative potential, preventing the cell from being able to produce an excitatory electrical pulse. The receptor that is believed to be a primary target for anesthetics is the GABA subtype A, or GABAa, receptor, which is also known to underlie the ther­apeutic effects of other classes of sedative and hypnotic drugs, most notably benzo-diazepines such as Valium. Very low con­centrations of benzodiazepines increase GABAa receptor function, a relation that is easily confirmed because reversal agents that impede benzodiazepine from binding to the GABAa receptor rapidly blunt the effects of those drugs. Unfortunately, no such reversal agents exist for general anesthetics that might provide clues to their receptor targets. Nevertheless, studies using slic­es from many different brain regions and neurons grown in tissue culture have shown that both intravenous and inhaled anesthetics prolong the dura­tion of postsynaptic electric currents generated by GABAa receptors. Anesthetics are believed to increase the function of GABAa receptors by in­teracting at discrete binding cavities or attaching to specifi c amino acids in the receptors themselves and prolonging the channel opening, which extends the in­hibitory effects of GABA molecules bound to the receptor. At high enough concentrations, anesthetics may even trigger the GABA receptors alone. The vast majority of neurons contain GABAa receptors, however, so scientists could not understand how anestheticsAnesthesia's Broad Impact Both the desirable and unwanted effects of anesthetic drugs stem from their power to suppress neuronal activity throughout the central nervous system, which encompasses the brain and spinal cord and controlsheart rate and breathing. Ongoing research is attempting to pinpoint the neural structures and regions whose changed functioning produces each of the defining properties of the anesthetized state.
Components of the Anesthetized State Sedation Reduced arousability, as evidenced by longer response times, slurred speech and decreased movement. Neuronal activity across brain cortical areas drops. Unconsciousness (also called hypnosis) Impaired perception of, and response to, stimuli. Cortical depression is deeper than in sedation. Activity in the thalamus, an area important for integrating brain processes, also falls signifi cantly. Immobility Lack of movement in response to stimulation such as shaking or heat. Suppression of spinal cord neuronal activity is the main cause of this temporary paralysis, although the cerebellum, a motor control area, may also contribute. Amnesia Lack of recall for the anesthetized period. Many brain structures involved in memory formation, including the hippocampus, amygdala, prefrontal cortex and sensory and motor areas, exhibit anesthetic-induced changes. Others Muscle relaxation and lack of pain (analgesia) are sometimes included in defi nitions of the anesthetized state and are largely attributed to depression of spinal cord activity.
Jamming Transmissioncould selectively infl uence different brain regions until research breakthroughs over the past decade revealed that not all GABAa receptors are structurally or pharmacologically the same. The GABA a receptor is a protein complex composed of fi ve subunit parts, which can be mixed and matched in various combinations. At least 19 different GABAa receptor subunits exist in mam­mals, and most of those have variant sub­types, so the possible number of combi­nations is high. The subunits most com­monly seen in neurons, however, are the ones designated alpha, beta and gamma. In fact, most GABAa receptors are com­posed of two alpha subunits, two betas and one gamma, although sometimes a delta or epsilon subunit replaces the gamma, depending on the brain region. But the key discovery was that the recep­tor's subunit composition dramatically alters its pharmacological properties: just one subunit difference within a GABAa receptor's structure can deter­mine whether and how it will respond to a particular anesthetic drug. Because different GABAa receptor subtypes predominate in different brain regions, researchers are increasingly able to pinpoint how anesthetics produce specifi c effects in various parts of the central nervous system by examining how the drugs interact in those regions with their particular target receptors. Narrowing Down Targets my colleagues and I decided to fo­cus on identifying the receptors that in­fl uence the memory-impairing proper­ties of anesthetics, so we concentrated our studies on GABAa receptors in the hippocampus. Anesthetics are known to cause amnesia at doses considerably lower than those required for uncon­sciousness or immobility, an effect that is clearly evident to anesthesiologists, for example, because patients rarely re­member their own animated conversa­tions as they go under or emerge from anesthesia. Yet, for unknown reasons, some patients experience unexpected recall of events during the surgery itself. Thus, by fi nding the correct target re­ceptors for the amnesia-inducing effects Anesthetic drugs have been found to dampen neuronal communication, in part, by enhancing the effects of the neurotransmitter GABA, a signaling molecule that inhibits nerve cells from fi ring. Current research is focused on how the drugs interact with cellular GABA receptors to block neural activity. Signal to Be Silent An electrical pulse in the membrane of one neuron provokes release of G ABA into the synapse, a juncture with another neuron. The molecules cross a small gap and bind to GABA-specifi c receptors on the postsynaptic cell. In many brain areas, GABA receptors are also found outside the synapse, along the nerve cell body, and are activated by GABA that spills out of the synapse.
Presynaptic neuron
Synapse
, Postsynaptic neuron
Extrasynaptic GABA receptor GABA receptor
Receptor subunits
Anesthesia molecule
Hyperpolarized cell membrane

Negative
Anesthetics and GABA: Changing Charge A receptor subtype called GABAa is a channel into the postsynaptic cell composed of five protein subunits. When GABA binds to it, the receptor opens to admit negatively charged ions, which increases polarization of the cell's membrane and prevents the neuron from generating an electrical pulse (left). Anesthetics are thought to act by binding to clefts in the GABAa receptor and prolonging the channel opening, which causes hyperpolarization of the cell membrane (right).

of anesthesia, it may become possible to identify patients at risk for intraopera-tive awareness because they lack those receptors. Alternatively, drug strategies to prevent awareness or at least its recol­lection could also be developed. In the course of this work, we discov­ered to our surprise that even receptors outside the synapse could play a role in anesthetic action. If the synapse serves as a switchboard at the junction between two cells, then receptors at the synapse periphery or scattered along the nerveRather than provoking a response at the "switchboard," the drugs were acting to boost a kind of static or inhibitory buzz in the telephone line itself that interfered with communication. We found that the injectable anes­thetics propofol and etomidate, and even the inhaled anesthetic isoflurane, in­creased the amplitude of this current by as much as 3 5-fold at concentrations sev­eral times lower than those required to cause immobility. Other investigators, including Stephen G. Brickley, Markon other research questions had also in­dicated that GABAa receptors contain­ing the alpha-5 subunit are involved in normal hippocampal-dependent memo­ry processes, supporting our theory that the extrasynaptic alpha-5 receptors were responsible for the memory effects of an anesthetic. To test our hypothesis fur­ther, we turned to experimenting with genetically modifi ed mice that lacked the alpha-5 subunit and wild-type mice that had the normal receptor. As expect­ed, in behavioral tests the wild-type
i rug strategies to prevent awareness or at least its recollection could be developed.
cell body can be imagined as residing on the telephone line itself. Such extrasyn­aptic GABAa receptors are activated by even the very low concentrations of GABA that are naturally present in the extracellular space or that spill over from nearby synapses. As it turns out, high numbers of extrasynaptic receptors are found in certain brain regions, such as the hippocampus and the thalamus (an area involved in consciousness and pain processing), as well as parts of the cortex and the cerebellum. We serendipitously learned the rele­vance of extrasynaptic GABAa recep­tors as anesthetic targets after struggling unsuccessfully for quite some time to identify postsynaptic receptors that were sensitive to the very low amnesia-induc­ing concentrations of anesthetics. We had also searched for populations of postsynaptic receptors that were syner-gistically modulated by midazolam and propofol, two of the most commonly used intravenous neurodepressive drugs, and had not found any of those either. Our work, however, was based on tak­ing electrophysiological recordings of currents generated in hippocampal neu­rons in tissue culture, and we did notice that amnesia-producing concentrations of anesthetics signifi cantly increased a persistent low-amplitude current gener­ated by extrasynaptic GABAa receptors.Farrant and their colleagues at University College London, had already described this steady low current even in the ab­sence of anesthetics. But what surprised our group was the extrasynaptic recep­tors' remarkable sensitivity to tiny amounts of both inhaled and intrave­nous anesthetics, whereas the low con­centrations of anesthetics caused only negligible changes in postsynaptic cur­rents. Previous studies, such as our own, had apparently focused on the right fam­ily of receptor proteins but were looking in the wrong location. Eventually our experiments deter­mined that the extrasynaptic GABAa re­ceptors were structurally slightly differ­ent from the populations of receptors within the synapse in that they predomi­nantly contained an alpha-5 subunit, which the postsynaptic receptors gener­ally lacked. That single change seemed to account for their sensitivity to even tiny amounts of anesthetics. These results were exciting to us because accumulating evidence from neuroscientists workingmice were sensitive to amnesia-causing doses of etomidate, whereas the alpha-5-deficient mice failed to manifest the drug's effects on memory. We also established that the loss of alpha-5 GABAa receptors had no conse­quences for any of the other anesthesia end points: sedation, immobility, hypno­sis and response to a painful stimulus were the same in both groups of mice. These results demonstrated that the memory-impairing effects of etomidate could be dissociated from the drug's oth­er properties based on the pharmacology of specifi c receptor subunits. They also provided the fi rst animal model for re­ceptor variations that might occur in hu­mans and could explain some cases of resistance to an anesthetic's ability to in­duce amnesia. Ongoing studies will de­termine whether other general anesthet­ic drugs also preferentially target alpha-5 GABAa receptors to produce amnesia. At the same time, laboratories in Eu­rope and the U.S. have been employing similar experimental techniques to ex- BEVERLEY A. ORSER is professor of anesthesiology and physiology at the University of Toronto and a practicing anesthesiologist at the university's hospital, the Sunny brook Health Sciences Center, where she is also Canada Research Chair in anesthesia. As both a clinician and researcher, Orser focuses on improving patient safety. By study ing the molecular mechanisms under lying anesthetic drugs, she hopes to advance development of new agents and related therapies with mo re fi nely controlled effects. Orser also con­sults for the pharmaceutical company Merck, developer of the sleep aid Gaboxadol.

Risk-Management Tools Before surgery with general anesthesia, a patient will see and be attached to an array of monitoring devices. Many of them are there to guard against side effects of the anesthetics, which depress breathing and heart function, lowering blood pressure and body temperature. An anesthesiologist must constantly calibrate drug delivery to achieve the desired depth of anesthesia without subduing the patient's cardiac and respiratory functions enough to risk death. Breathing circuit------------- Delivers oxygen and air mixed with inhaled anesthetics through one tube; removes exhaled gases through the other tube
Electrocardiograph electrodes Applied to chest and limbs to track heart electrical activity and rate
Warming blanket Provides forced hot air to maintain body temperature. Blood and intravenous fl uid warmers are also commonly used Not shown: Temperature probe Applied to the skin or inserted into the esophagus or rectum, depending on type and length of surgery Arterial catheter Inserted into artery in wrist or groin. Provides beat-to-beat measurement of blood pressure and allows frequent blood sampling
Pulse oximeter probe Clipped to fi nger or ear to measure blood oxygen level
Intravenous line Delivers intravenous anesthetics and fl uids

plore the hypnotic and immobilizing ef­fects of anesthetics. Gregg E. Homanics of the University of Pittsburgh School of Medicine, for example, developed a mouse lacking the GABAa receptor del­ta subunit, which is known to confer high sensitivity to neurosteroids. His group's investigation found that the del­ta-defi cient mice were, predictably, less sensitive to the steroid-based anesthetic alphaxalone in tests of the drug's power to induce unconsciousness. The mutant mice, however, displayed no differences in their responses to propofol, etomi-date and other nonsteroidal anesthetics as compared with wild-type controls. Steroid anesthetics are not commonly used today, but these results also dem­onstrated the principle that different classes of anesthetics target discrete subpopulations of GABAa receptors. Such experiments have truly over-turned the old notion that because anes­thetics are so chemically different from one another they must produce their multiple effects by some general mecha­nism. Instead empirical development of anesthetic drugs seems to have stumbled on chemicals that produce similar end points, though each by its own unique mechanisms. Etomidate, for example, is the only anesthetic in clinical use that is selective for GABAa receptors containing the beta-2 or beta-3, but not the beta-1, sub-unit. Indeed, the differences between the beta-subunit variants that respond to etomidate and those that do not in­volve a single amino acid change at a specifi c point in the subunit's protein structure. The pharmaceutical compa­ny Merck developed transgenic mice with a mutation in that amino acid loca­tion within the beta-2 subunit and foundthat etomidate was less effective at pro­ducing unconsciousness in the animals; the drug's immobilizing properties re­mained, however. Uwe Rudolph, while at the University of Zurich, also gener­ated transgenic mice with the same mu­tation in the beta-3 subunit and found that it greatly diminished the effective­ness of both etomidate and propofol in producing unconsciousness and analge­sia in the animals. In contrast, he showed that alphaxalone was equally effective in wild-type mice and those carrying the mutation, which indicates that these receptor subunits are proba­bly not important targets of that drug. Whether the point mutations in beta-2 and beta-3 receptor subunits also in­fluence the drugs' amnesia-inducing properties has not yet been established. And which central nervous system re­gions in the transgenic mice are affected
is now being studied as a sleep-promoting drug. It targets GABAa receptors con­taining the delta subunit, primarily found in the thalamus and cerebellum, and therefore may also avoid affecting memory. The memory-blocking poten­tial of similar compounds that do inter­act with alpha-5 receptors could also prove very useful in the surgical setting, where drugs that cause profound amne­sia without depressing respiration, air­way refl exes or the cardiovascular system might be highly desirable. In combina­tion with other anesthetics, a potent memory blocker could be used to prevent intraoperative awareness episodes, for example. Alone, such a drug might be helpful in the treatment of patients suf­fering post-traumatic stress disorder by inhibiting certain distressing memories. Management of anesthesia's effects on memory is just one example of a new approach to anesthesiology that will be­come possible with such targeted drugs. In many situations, the broad and pro­found neurodepression of current anes­thetics is unnecessary and undesirable anyway. With a cocktail of compounds, each of which produces only one desir­able end point, the future version of an­esthesia care could leave a patient con­versant but pain-free while having a broken limb repaired or immobile and sedated but aware while having a hip replaced. This polypharmaceutical ap­proach is already widely used for other aspects of surgery-related care, most notably in the treatment of postopera­tive pain. Today anesthesia has never been saf­er, but it is certainly not without risk. A tremendous opportunity now exists for the fi eld to move beyond the ether era and toward a truly modern model of an­esthesia care. && Capnograph monitor Displays measurements of exhaled carbon dioxide to ensure ventilation is appropriate
Gas sampler Monitors oxygen, carbon dioxide and anesthetic concentrations in both inhaled and exhaled air
Vaporizers Store and blend the inhaled anesthetics in exact desired concentrations Anesthesia delivery monitor
Anesthesia fl ow controls
Anesthesia delivery unit Combines inhaled anesthetics with oxygen and room air and controls their fl ow. Alarm system detects disconnection of the breathing circuit or changes in levels of inhaled oxygen. Also scavenges exhaled carbon dioxide and anesthetic gases so they do not contaminate the operating room
by the mutations is another unknown, although some evidence suggests that ex-trasynaptic GABAa receptors in the thalamus may be critical. Taken together, however, such studies are confi rming the central role of GABAa receptors in the actions of anesthetics. The next step is to begin translating this knowledge gained from current general anesthetics into drugs that are anything but general. Tailored Treatment as the work of my research group and others has shown, extrasynaptic al-pha-5 GABAa receptors in the hippo­campus are vital to the amnesia-induc­ing effects of etomidate and possibly to other general anesthetics currently in use. These results suggest that drugs that avoid or target that particular re­ceptor could selectively spare or block memory formation as needed.In fact, such compounds are already in development for other uses. Sedative-hypnotic drugs that do not act on the al-pha-5 subunit, and hence should lack the memory-fuzzing effects of benzodiaze-pine sedatives and certain sleeping pills, are in the preclinical pipeline. And clini­cal trials of Gaboxadol, the fi rst drug to selectively target extrasynaptic GABAa receptors to enhance their function, are currently under way. Gaboxadol was ini­tially developed as an anticonvulsant but MORE TO EXPLORE Anesthesia Safety: Model or Myth? Robert S. Lagasse in Anesthesiology, Vol. 97, pages 1609-1617; December 2002. Molecular and Neuronal Substrates for General Anaesthetics. Uwe Rudolph and Bernd Antkowiak in Nature Reviews Neuroscience, Vol. 5, pages 709-720; September 2004. Emerging Molecular Mechanisms of General Anesthetic Act ion. Hugh C. Hemmings et al. in Trends in Pharmacological Sciences, Vol. 6, No. 10, pages 503-510; October 2005. ct5 GABAa Receptors Mediate the Amnestic but Not Sedative-Hypnotic Effects of the General Anesthetic Etomidate. Victor Y. Cheng et al. in Journal of Neuroscience, Vol. 26, No. 14, pages 3713-3720; April 5, 2006