Human Molecular Genetics, 2002, Vol. 11, No. 10 1241-1249
© 2002 Oxford University Press
Understanding anesthesia: making genetic sense of the absence of senses
1Departments of Genetics and Anesthesiology, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH 44106, USA
Received March 4, 2002; Accepted March 4, 2002
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ABSTRACT |
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 TOP ABSTRACT SACCHAROMYCES CEREVISIAECAENORHABDITIS ELEGANSDROSOPHILA MELANOGASTERMAMMALSSUMMARYREFERENCES |
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The discovery of the phenomenon of anesthesia over 150 years ago was a watershed event that revolutionized the practice of medicine. Despite their annual use in millions of patients, the mechanism by which volatile anesthetics produce reversible loss of consciousness remains a mystery. The inherent problems in studying loss of consciousness in humans are legion. However, multiple model organisms are currently being exploited to apply the powerful tools of modern molecular genetics to this question. Mutants in yeast, nematodes, fruit flies and mice have been produced that display abnormalities in their response to volatile anesthetics. Each organism possesses unique advantages and difficulties as a model system, and each reveals different molecules that control its response to anesthetics. Nonetheless, the accumulating body of genetic evidence points to multiple targets for volatile anesthetics. Not only will understanding how volatile anesthetics work yield better and safer anesthetics, but, in addition, these remarkable compounds may ultimately serve as probes to understand the nature of consciousness itself.
Anesthesia is a physiological state defined by four main features: amnesia, analgesia, muscle relaxation and loss of consciousness. These can be produced separately or in various combinations, but only when all four are present has general anesthesia been achieved. Since anesthesia is a combination of behavioral endpoints, it is impossible to measure without an intact organism.
The single agents that are capable of causing complete anesthesia are the volatile anesthetics (VAs). Although in continuous usage for the past 150 years, and despite considerable effort, a convincing hypothesis has yet to emerge that explains the mechanisms of VA action (1,2). There are two primary reasons for this failure. First, loss of consciousness (one of the components of anesthesia) is difficult to measure or even define. Second, VAs are thought to bind with low affinity to many targets, some of which are undoubtedly not involved in producing the anesthetic state. Thus, despite producing physiologic effects at many potential sites of action, it is difficult to know which of these effects contribute to anesthesia.
The volatile agents capable of producing anesthesia are structurally diverse, ranging from simple compounds such as the noble gas xenon to more complicated halogenated compounds such as halothane (Fig. 1). However, one strong physical correlation, the Meyer–Overton relationship, does exist. This correlation, known since the beginning of the 20th century, relates anesthetic potency to lipid solubility (3,4). The more lipid-soluble a VA is, the more potent it is. These observations led to the ‘unitary hypothesis’: that all VAs work by essentially the same mechanism – a non-specific perturbation of lipids within excitable cellular membranes. However, the magnitudes of the membrane changes caused by the anesthetics (such as membrane volume or fluidity) are less than the changes seen on varying body temperature a few degrees.
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The lack of significant changes caused by VAs in artificial membranes led to the consideration that the anesthetic targets might involve other molecular species. Abraham, Franks and Lieb (5) observed that anesthetic potency correlated very well to the solubility of the VAs in octanol. In addition, investigators have now shown significant differences in efficacy between stereoisomers of specific anesthetics (2,6). Finally, there exist a series of compounds called non-immobilizers that by their lipid solubilities are predicted to be VAs but that display little or no anesthetic potency in mammals (7). As a group, these observations have led to the conclusion that an anesthetic site of action can differentiate between molecular shapes, and may also contain both non-polar and polar properties. As a result, proteins are currently favored over lipids as probable anesthetic targets (1,2). However, a recent paper by Cantor (8) has revisited this conclusion and presented evidence that interactions between lipids and VAs may yet play an important role in anesthetic action.
Besides a change in consideration of the molecular nature of an anesthetic target, genetic evidence is accumulating that challenges the unitary hypothesis (9,10). Mutations have now been isolated in several organisms that change sensitivity only to specific VAs. It follows that if various molecular sites affect sensitivity to specific VAs, then the unitary hypothesis of general anesthesia is an oversimplification. The functions of a great number of molecules are changed by VAs. A genetic approach can potentially sort out which molecules actually contribute to the state of anesthesia, which is ultimately a whole-animal behavior. Currently, a genetic approach to understanding anesthetic action is being pursued in four organisms: the yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the mouse Mus musculus. Their advantages and disadvantages (and those of humans) as model systems in which we study anesthetic action are listed in Table 1. Below, we detail these studies, from simple to complex model organisms.
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Keil and colleagues (11) have studied the effects of VAs on the yeast S. cerevisiae. Yeast may seem an unusual system in which to study phenomena normally attributed to the nervous system. However, the interactions of VAs with well-defined molecules may reveal common molecular themes shared with more complicated organisms. The authors found that all VAs inhibit growth in yeast, at concentrations approximately 10 times those required for surgical anesthesia in mammals. The inhibiting concentrations followed the Meyer–Overton relationship. In addition, the endpoint chosen by the authors is reversible, is not affected by non-immobilizers and displays several other characteristics of anesthetic affects on organisms with nervous systems.
Keil and colleagues isolated a single mutation, termed zzz4, that conferred resistance to the inhibition of growth by isoflurane. The protein ZZZ4 is a membrane protein whose amino acid structure is homologous to that of a rodent phospholipase A1-activating protein (PLAP) and that is involved in degradation of ubiquinated proteins. PLAP itself is homologous to G proteins, and so falls into one class of candidates proposed to be affected by VAs (12). The authors have also identified two other genes that can be mutated to alter anesthetic sensitivity in yeast. One codes for a protein that binds ubiquitin ligase and the other one codes for the protein ubiquitin ligase itself (12). Studies in yeast clearly indicate a role for ubiquitin metabolism in controlling the sensitivity to VAs in yeast. It remains to be seen whether homologues of this class of protein also affect anesthetic sensitivities in organisms with nervous systems. However, an interesting association of ubiquitin ligase with lipid rafts has been noted in MCDK (Madin–Darby canine kidney) cells (13), which may correlate with results discussed below.
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The nematode C. elegans has a well-defined nervous system and multiple behaviors, which can be used as anesthetic endpoints (14,15). Wild-type nematodes, N2, move constantly in a sinuous motion on an agar plate. When exposed to VAs, they first increase movement, become ‘excited’, and lose their response to volatile attractants. This behavior proceeds to a progressive lack of coordination, followed by immobility and unresponsiveness to a tap to the snout (14). This progression of neurologic changes is reminiscent of the neurological responses seen in mammals (Fig. 2). Two different endpoints have been used to measure anesthetic effects in C. elegans. The first endpoint studied is complete immobility of the animal for 10 seconds (Fig. 3). The second endpoint used is radial dispersion, the ability of a nematode to move radially from a starting point in the center of a plate of agar towards a peripheral ring of food. The percentage of nematodes reaching the food in the presence of a VA serves as the endpoint (15). The loss of function associated with both endpoints is quickly reversed upon removal of the worms from the anesthetic agent; subsequent lifespan, fertility, movement, chemotaxis and mating are unaffected by exposure to these agents (14,15). The dose of anesthetic necessary to cause an absence of movement in response to a noxious stimulus in 50% of humans (an EC50) is termed the minimum alveolar concentration, or MAC. The absolute dose of anesthetic required to cause immobility in C. elegans is higher than MAC in mammals, while that required for loss of radial dispersion is similar to MAC. The ratio of the lethal dose to the effective dose for immobility is approximately 2.5, similar to that for VAs in mammals (16), while that for radial dispersion is approximately 20. Strengths and weaknesses exist for both endpoints as a model for MAC. However, both endpoints follow the Meyer–Overton relationship very closely (14,15). As noted earlier for mammals, non-immobilizers (8) also failed to immobilize C. elegans (17) and stereoisomers of VAs exhibit different potencies in C. elegans when immobility is used as an endpoint (18).
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Immobility
The first identified mutant with profound changes in anesthetic sensitivity, using immobility as the endpoint, was unc-79 (14,19). Mutations in unc-79 cause a striking hypersensitivity to the four most lipid-soluble VAs, but either no change or resistance to other VAs (20). unc-79 animals showed decreased binding of the anesthetic halothane (RG Eckenhoff, personal communication). Since unc-79 deviates from the Meyer–Overton rule, it follows that the unitary hypothesis is an oversimplification.
The X-linked mutation unc-1(0) suppressed unc-79, i.e. when grouped with unc-79 it restored to normal the hypersensitivity of unc-79 to the most lipid-soluble anesthetics (21). unc-1 also restored the resistance of unc-79 to two VAs back to normal, and left unchanged any responses that were identical between mutants and wild type. However, it did not return to baseline the changed response of unc-79 to diethyl ether. unc-1(0) is similar to N2 in anesthetic response, except for an approximately 30% increase in sensitivity to diethyl ether and a 5–10% resistance to halothane. These data all support the interpretation of the original unc-79 data, i.e. that multiple sites of action exist for VAs.
unc-1 has complicated interallelic interactions affecting both motion and anesthetic sensitivity. These interactions indicate that the protein UNC-1, probably functions in a multimeric protein complex (22,23). The unc-1 gene encodes a homologue of a human protein, stomatin (24). Stomatin is an integral membrane protein in humans that is expressed within many types of cells (25), and controls sodium and potassium flux across membranes. However, its exact mode of action is not known. UNC-1 is expressed in the nervous system (Fig. 4) and interacts with a class of epithelial sodium channels (termed ENaCs). Mutations in these sodium channels (encoded by the gene unc-8) also directly alter anesthetic sensitivity in patterns similar to those found with unc-1 (23,26).
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Recent studies in both mammals and C. elegans indicated that stomatin is localized to lipid microdomains found in cell membranes termed lipid rafts (27,28, P.G. Morgan and M.M. Sedensky, unpublished data), and may be partly responsible for the formation and maintenance of these rafts (29). Lipid rafts are microdomains in the cell membrane with increased amounts of sphingolipids and cholesterol and are thought to localize multiple membrane proteins into complexes. Mutations in stomatin and stomatin-like proteins could exert their effects by disruption of membrane associated lipid domains and their associated protein complexes. Morgan and Sedensky isolated lipid rafts in C. elegans and found that stomatin also localizes to these domains. In addition, a mutation in a gene called unc-24 blocks the movement of UNC-1 (and presumably the associated rafts) from the perinuclear region to the cellular membrane. unc-24 mimics the unc-1 loss-of-function phenotype both in air and in anesthetics (30). Lipid rafts may therefore serve as a unifying target that requires both the lipid solubility of VAs and their specific properties that implicate protein interactions. The list of proteins associated with lipid rafts includes ligand-gated channels, G-protein-coupled receptors and members of the SNARE complex (31–33). Each of these has been postulated to be a target of VAs.
Another mutation, gas-1(fc21), causes C. elegans to be hypersensitive to all VAs tested, despite normal motion in air (34). The gas-1 gene encodes the 49 kDa(IP) subunit of the mitochondrial NADH:ubiquinone–oxidoreductase (complex I of the respiratory chain) (35). It is a member of a very large protein complex that is the first step of electron transport. Metabolic studies show that the function of complex I is reduced in gas-1 mutants and that anesthetics further decrease the function of this complex (36,37). Interestingly, a mutation in complex II of the electron transport chain (36) (mev-1) does not affect the function of complex I and does not alter anesthetic sensitivity (38,39). Complex II feeds electrons into the same acceptor as complex l, i.e. it is a separate way to donate electrons to coenzyme Q. The finding that a mutation in complex I increases the sensitivity of C. elegans to Vas, while a mutation in complex II does not, implicates this particular step in electron transport in the determination of anesthetic sensitivity. The contribution of mitochondrial proteins to anesthetic response is particularly interesting, since previous work in mammalian systems has also shown that com-plex I-dependent oxidative phosphorylation is sensitive to VAs (40).
Radial dispersion
Crowder and colleagues (15,41) have screened nematodes carrying previously identified mutations in neuronal proteins of C. elegans for altered sensitivity to anesthetics using radial dispersion as the endpoint. They found that a mutation in syntaxin dominantly conferred resistance to the VAs isoflurane and halothane. Syntaxin is a member of the protein complex that controls presynaptic vesicular fusion with the cell membrane, resulting in neurotransmitter release into the synaptic cleft (42). This complex is termed the SNARE complex and includes the syntaxin-binding proteins synaptobrevin and SNAP-25 (43,44). Mutations in these other proteins failed to produce VA hypersensitivity. The syntaxin allelic variation was striking, particularly for isoflurane, where a 33-fold range of sensitivities was seen. Both the resistant and hypersensitive mutations decrease synaptic transmission; thus, the indirect effect of reducing neurotransmission does not explain the anesthetic resistance. These results were consistent with a protein target for VAs and implicate syntaxin as a possible anesthetic target. Crowder and Berilgen (45) have also presented data showing that mammalian syntaxin is capable of binding halothane.
It is interesting that the members of the SNARE complex have been found to be associated with lipid rafts and with ENaC channels (33,46). Syntaxin mutations do not alter anesthetic sensitivity when immobility is used as an endpoint (P.G. Morgan and M.M. Sedensky, unpublished data). However, the association of the SNARE complex, stomatin and ENaC channels with lipid rafts and with each other suggests a common pathway or target affected by these mutations. These data are further emphasized by the fact that the system identified in yeast, the ubiquitin system, has also been shown to reside in lipid rafts (13). Thus, proteins identified by diverse screens may implicate targets associated with lipid rafts in both yeast and in C. elegans.
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DROSOPHILA MELANOGASTER |
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TOPABSTRACTSACCHAROMYCES CEREVISIAECAENORHABDITIS ELEGANSDROSOPHILA MELANOGASTERMAMMALSSUMMARYREFERENCES |
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As a genetic model, Drosophila is the historic paragon, possessing a high density of genetic markers, completely sequenced genome, and easy-to-identify behaviors and morphology. In addition, as in the nematode, there is a high degree of conservation between genes in the fly and in mammals. The nervous system is more complicated than that of the nematode, which serves as a mixed blessing. On the one hand, the behaviors of the fly are likely to result from an increased level of complexity in neuronal connections – more like that of a mammal. However, as might be expected, this increased complexity may make it more difficult to trace genetic changes to specific neurons or groups of neurons.
Gamo and colleagues (9) pioneered the use of Drosophila by studying the sensitivity of the fly to diethyl ether using non-responsiveness to touch as the endpoint. They identified a mutation in the 
subunit of a sodium channel that caused the altered sensitivity (47). However, no further work on this mutation has been reported. Krishnan and Nash (48) screened extensively for mutations that alter anesthetic sensitivity in Drosophila by scoring the posture or movement of the flies in anesthetics. Using this endpoint, they identified a group of four mutations, known as har (halothane-resistant) mutants. Like some of the nematode mutants, the har mutants alter sensitivity to some VAs differently than others. These findings are most consistent with multiple sites of anesthetic action.
A potential pitfall in conducting a genetic screen for VA sensitivity is the inability to differentiate between mutations that affect an anesthetic target from those that have effects either upstream or downstream of the target. In an attempt to differentiate between these two possibilities, Nash and colleagues (49–52) also studied several other anesthetic endpoints in flies. They reported that the changes in sensitivity in har mutants are dependent on the assay used, i.e. the mutants exhibited differential changes in sensitivity when the endpoint was varied (49,50). They used an intense beam of light (50) or direct electrical signals to the eye (53) to assess the effect of the har mutations on the capacity of fruit flies to sense a noxious stimulus and respond to it. These results were compared to the earlier studies using changes in posture and movement described above. Undoubtedly, such results represent layers of integrated neuronal interactions that produce a complex behavioral response. As previously discussed, complex behaviors can be changed by mutations that have indirect effects on the phenomenon of anesthesia. Nash and colleagues hope to isolate mutations that are as close as possible to the actual target of VAs by studying a defined cellular physiology. Consequently, they have pursued the study of a variety of simple, well-defined reflexes of Drosophila in order to test the effects of VAs on specific neuronal circuits.
Nishikawa and Kidokoro (54) studied the effects of two har mutations on synaptic transmission at the larval neuromuscular junction. They found that halothane decreased the frequency of glutaminergic miniature excitatory junctional currents in the wild-type synapse, but that it did not change the frequency in synapses from the mutants har38 and har85. These results indicate that this glutamate-mediated pathway is important in determining halothane sensitivity in flies and that at least two of the har mutants alter sensitivity by affecting this pathway. The exact role of the genes in this pathway defined by har38 and har85 awaits molecular data characterizing their gene products.
In addition to the har mutants, Nash and colleagues studied several known mutants as controls for their choice of endpoints. Using the escape response as another well-defined neuronal circuit in which to test the effects of VAs, Walcourt and Nash (52) have shown that mushroom body defect (mud) mutants have an increased sensitivity to halothane. These animals have a variety of changes in brain structure, although gross changes in brain anatomy did not correlate with anesthetic sensitivity. Similarly to the har mutants, changes in anesthetic sensitivity of mud mutants differ between the three tested anesthetics. Interestingly, several other mutations causing global changes in brain structure did not alter anesthetic sensitivity. Thus, the circuit affected by mud seems to be specifically sensitive to anesthetics and to be a good model for identifying genes affecting anesthetic response of a behavior with a much simpler level of complexity. Nash's group (55) recently studied the affects of changes in the potassium channel encoded by the Shaker gene on the escape pathway. They found that Shaker had profound effects on the response of this circuit to halothane. Using a well-defined neuronal circuit, such as the escape response, may in fact be very important in isolating an effect of VAs that is close to the anesthetic target.
Using a movement based assay, Campbell and Nash (56) found that two genes, brown and white, previously thought to be responsible only for eye color, also have neurobiological functions. These genes encode ABC transporters traditionally believed to form a plasma-membrane-associated heterodimer responsible for pumping guanine into cells. The guanine could be processed into cGMP and affect a host of neurotransmitters. However, other researchers have presented data consistent with the theory that White may be a member of a complicated pathway involving lipid metabolism (57).
These studies emphasize both the power of genetic approaches and the importance of correlation of the findings to other methods of characterizing anesthetic action. In Drosophila, the classic genetic approach of Nash and colleagues has been greatly aided by the neurophysiologic studies of the har mutants, the studies of flies with defined anatomical defects in the brain, and by studies of flies with changes in specific ion channels. As seen in nematodes, the initial findings implicate sites that are not obvious choices as anesthetic targets.
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MAMMALS |
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Mammals such as rats or mice have behaviors that can unequivocally be related to human MAC. In addition, the organization of neuronal pathways in rodents more clearly approximates that of man than the neuronal pathways of C. elegans or Drosophila. Mice also possess some unique advantages compared with simpler model systems. (i) Various ‘wild-type’ strains have different anesthetic sensitivities that can be used to address the question of how VAs work. (ii) Recombinant inbred (RI) strains have already been made in the mouse and rat that have different sensitivities to alcohol or benzodiazepines. These RI strains have been studied for their effects on anesthetic sensitivity. (iii) Targeted mutations can be made in mice to test the importance of specific genes in determining anesthetic sensitivity. Each of these examples is discussed below.
Mus musculus
Eger and colleagues (58,59) measured the naturally occurring variability in anesthetic potency, defined by MAC, required to produce immobility in response to noxious stimuli. They studied 15 commonly used laboratory mouse strains, and found that mice could differ in MAC by 39–55% for different VAs. It is remarkable to realize that these various wild-type strains of the same species have such widely differing responses to VAs. One hundred and forty-six statistically significant differences among the 15 strains were found for the three inhaled anesthetics tested. Eger and colleagues concluded that multiple genes underlie the observed variability in anesthetic potency. This is consistent with the hypothesis that multiple targets exist for these anesthetics. Properly studied, however, the differences between wild-type strains have the potential to narrow down the search for anesthetic sites of action by focusing our attention on the genetic differences between wild-type strains.
The mechanism of action of ethanol has been intensely studied in RI strains of mice. Several laboratories have used mouse strains with increased (LS, long sleep) and decreased (SS, short sleep) sensitivity to ethanol for studies of VA sensitivity (60). The sensitivity of these strains to VAs varies with the anesthetic studied. Erwin and colleagues (61) found that sensitivity to ether did not increase in LS mice compared with SS mice. Similarly, Baker and colleagues (62) found that sensitivity to halothane was not increased in LS mice. However, Koblin and Deady (63) showed that LS mice did have increased sensitivities to enflurane and isoflurane. These studies are most consistent with there being multiple sites of anesthetic action for VAs. However, at least nine genetic loci are estimated to vary between the LS and SS lines. In vitro studies have implicated the GABAA receptor as one of many contributing targets to the variation in ethanol response (64), but the identity of the remaining loci is unknown (65,66).
Similar results have recently been obtained using rat lines bred for altered sensitivity to ethanol. Firestone and colleagues (67) studied the response of these strains to the VAs halothane and desflurane, and found that their responses to halothane differed from those to desflurane. They concluded that their data support the hypothesis that different anesthetic endpoints are produced by separate mechanisms.
The GABAA receptor is a channel shown to be affected by VAs in isolated cells. As a result, targeted mutations in the GABAA receptor have been studied in the mouse. Firestone and colleagues have created several knockouts affecting different subunits of the GABAA receptor. Mice completely lacking the ß3 subunit of the GABAA receptor (ß3-/-) did not differ from wild-type mice (ß3+/+) in the obtunding response to enflurane and halothane, but were mildly resistant (10–20%) to enflurane and halothane as determined by tail clamp response (68). However, these animals also demonstrated a generalized loss of nociception in the absence of anesthetic (69). When the effects of loss of the 6 subunit were tested, no differences between wild type and mutant were seen (70). Questions inevitably arise, however, as to possible redundancy or compensatory changes in subunit expression, synaptic wiring, etc. in these complicated systems. The complexity of the organism, which makes it a good model for human behavior, is not an unmitigated blessing. Mutations in single genes may not produce a striking phenotype in mammals.
Homo sapiens
Prospective studies to identify genetic differences in sensitivity to VAs in humans have not been done. Recently, however, Morgan and colleagues (71) have identified a subset of patients with mitochondrial defects who are profoundly more sensitive to sevoflurane, as judged by the concentration of the VA necessary to reach consistent depression of their EEGs. Remarkably, the findings in C. elegans are corroborated by observations in humans. This confirms the potential applicability of studies in model organisms to a human disease process.
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SUMMARY |
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TOPABSTRACTSACCHAROMYCES CEREVISIAECAENORHABDITIS ELEGANSDROSOPHILA MELANOGASTERMAMMALSSUMMARYREFERENCES |
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Genetic data are beginning to form the picture of the molecular sites that control anesthetic sensitivity. At present, the mutations identified are most consistent with protein targets, though a contribution by lipid species is a strong possibility. The genetic studies described above strongly suggest that anesthetic response is dependent on a broad group of molecular targets or pathways. The finding of altered sensitivity in patients with mitochondrial disease underscores the applicability of these studies to the human population.
It is also interesting to note what genetic data fail to do. They do not identify a single protein or channel that is uniquely responsible for the effects of anesthetics. The many endpoints associated with the anesthetic state are probably the result of effects at different sites of anesthetic action. In addition, even when considering a defined simple endpoint, the VAs behave differently from each other. This indicates that, even with single endpoints, multiple targets or mechanisms are involved. We are beginning to identify physical properties that are common between possible anesthetic targets. However, additional genes that affect anesthetic sensitivity will certainly still be identified. Among those that have been characterized, there still exists a diversity that is difficult to mold into a common theme. The continuing advances in characterization of the human genome will certainly accelerate the synthesis of knowledge gained from model systems to illuminate one of pharmacology's oldest riddles.
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ACKNOWLEDGEMENTS |
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We should like to thank Howard Nash for his comments and suggestions concerning this review. The authors were supported by NIH Grants GM45402 and GM58881 and by a grant from the Muscular Dystrophy Association.
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FOOTNOTES |
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* To whom correspondence should be addressed. Tel: +1 216 844 7340; Fax: 216-844-3781; Email: philip.morgan{at}uhhs.com
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REFERENCES |
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