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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.55 no.1 Campinas Jan./Feb. 2005
Immobility: essential inhalational anesthetics action*
Inmovilidad: una acción esencial de los anestésicos inhalatorios
Leonardo Teixeira Domingues Duarte, TSA, M.D.I; Renato Ângelo Saraiva, TSA, M.D.II
IAnestesiologista da Rede Sarah de
Hospitais do Aparelho Locomotor
IICoordenador de Anestesiologia da Rede Sarah de Hospitais do Aparelho Locomotor
BACKGROUND AND OBJECTIVES: Immobility
is an essential component of general anesthesia and should be looked for and
maintained throughout anesthesia. Anesthetic potency, called Minimum Alveolar
Concentration (MAC), results from the inhibition of movement response to noxious
stimulation. However, although spinal cord is recognized as the primary mediator
of surgical immobility, cellular and subcelular mechanisms of action of inhaled
anesthetics to produce immobility are not yet totally known. Considering major
research advances on mechanisms of action of inhaled anesthetics and resulting
wide variety of information, this review aimed at critically evaluating clinical
and experimental studies performed to identify sites of action and mechanisms
of inhaled anesthetics to promote immobility in response to noxious stimulations.
CONTENTS: Complex mechanisms of action of inhaled anesthetics on central nervous system may be divided into three levels: macroscopic, microscopic, and molecular. Macroscopically, behavioral studies have shown spinal cord to be the primary anesthetic site of action to promote immobility in response to noxious stimulations. At cellular level, excitability of motor neurons, nociceptive neurons and synaptic transmission are involved in the anesthetic action. At molecular level, several receptors are affected by inhaled anesthetics, but only a few may directly mediate anesthetic action, among them: glycine, glutamate AMPA and 5-HT2A receptors, in addition to voltage-gated sodium channels.
CONCLUSIONS: Inhaled anesthetics-induced immobility is primarily mediated by an action on the spinal cord, as a consequence of anesthetic action upon motor neurons excitability and upon nociceptive neurons of the spinal cord dorsal horn. Actions on specific receptors have an effect on their synaptic transmission.
Key words: ANESTHESIA, General: inhalational; MONITORING: anesthesia profundity
JUSTIFICATIVA Y OBJETIVOS: La inmovilidad
es una característica esencial de la anestesia general que debe ser buscada
y mantenida durante todo el acto anestésico. La potencia anestésica,
llamada Concentración Alveolar Mínima (CAM), es la expresión
de la inhibición de los movimientos en respuesta a estímulos nociceptivos.
Mientras, a pesar de la médula espinal ser reconocida como principal mediadora
de la inmovilidad quirúrgica, los mecanismos celulares y subcelulares de
la acción de los anestésicos inhalatorios para que produzcan inmovilidad
no son, aún, totalmente conocidos. Considerando el grande avance en la
pesquisa de los mecanismos de acción de los anestésicos inhalatorios
y el resultado de grande cantidad de informaciones, esa revisión tiene
como objetivo evaluar críticamente los estudios clínicos y experimentales
realizados para identificación de los mecanismos y locales de acción
de los anestésicos inhalatorios para producir inmovilidad como respuesta
a estímulos nociceptivos.
CONTENIDO: Los mecanismos de acción de los anestésicos inhalatorios en el SNC pueden ser divididos en tres niveles: macroscópico, microscópico y molecular. En el aspecto macroscópico, estudios comportamentales mostraron que la médula espinal es el principal local de la acción anestésica para promover inmovilidad en respuesta a la estimulación dolorosa. A nivel celular, la excitabilidad de los motoneuronios, neuronas nociceptivas y la transmisión sináptica están, todos, envueltos en la acción de los anestésicos inhalatorios. Bajo el punto de vista molecular, diversos receptores son afectados por los anestésicos, pero pocos deben mediar directamente la acción anestésica. Entre éstos, se destacan los receptores de glicina, NMDA de glutamato, 5-HT2A, y canales de sodio voltaje-dependientes.
CONCLUSIONES: La inmovilidad producida por los anestésicos inhalatorios es mediada, principalmente, a través de una acción sobre la médula espinal. Ese efecto ocurre por la acción anestésica sobre la excitabilidad de las neuronas motoras espinales, pero también sobre neuronas e interneuronas nociceptivas del cuerno posterior de la médula. La acción sobre receptores específicos ejerce efecto sobre la transmisión sináptica de esas neuronas.
General anesthesia is a pharmacological intervention to prevent adverse psychological and somatic effects of surgical trauma and also to create adequate surgical conditions 1. In general, it is defined as the triad of unconsciousness, amnesia and immobility in response to noxious stimulations 2.
Although being widely used, sites of action and mechanisms of general anesthesia are still unknown. However, the understanding of how inhalational anesthetics reversibly change central nervous system (CNS) functions has significantly evolved in the last two decades, through neurophysiologic in vivo and in vitro studies and genetic engineering techniques.
In the last decade, the observation that movements occurring during painful stimulation could not be anticipated by EEG monitoring has raised the hypothesis that electric cortical activity does not control motor responses 3,4. In addition, that the development of drugs able to suppress learning and memory without promoting immobility 5,6 is an additional evidence that components of the anesthetic status result from action sites other than the CNS 7,8. Compilation of studies of the early nineties with different research methods in animal species has clearly shown that the spinal cord (SC), although suffering supraspinal modulating influences 9,10, is the primary CNS site of action for inhalational anesthetics to promote immobility 11-13.
Studies on anesthetic mechanisms in the spinal cord have resulted in the identification of several cellular and subcelular structures that could be potential targets. Different clinical effects of anesthetics are probably due to actions on a small number of specific molecular targets, counteracting the classic opinion that all general anesthetics have nonspecific action.
The posterior horn of SC gray matter is a possible anesthetic site of action since posterior horn cells activity in response to noxious stimulations is depressed by volatile anesthetics 14-23. However, this is not the single SC site of action of inhalational anesthetics involved in motor response suppression. Synaptic transmission depression 24 and decreased spinal motor neuron excitability 25-28 are also responsible for the SC effects of inhalational anesthetics.
Genetic engineering techniques were developed to allow the study of specific receptors, both in SC posterior horn and in alpha motor neurons, in the search for specific molecular mechanisms of inhalational anesthetics to promote immobility. Initially, several receptors were implied in the genesis of immobility, but today it is known that only a few of them are directly involved 29.
The understanding of inhalational anesthetics mechanisms of action is a fascinating field in constant evolution, with new discoveries each day, but which, at the same time, remains partially unknown. Mechanisms through which inhalational anesthetics promote immobility, preventing movement response to surgical stimulation are still equally unknown, especially with regard to anesthetic action on cellular and molecular targets, which are numerous with unknown relative importance. This literature review aimed at presenting clinical and experimental studies performed to determine sites and mechanisms of actions of inhalational anesthetics to promote immobility, by analyzing macroscopic, microscopic and molecular aspects.
CLINICAL DEFINITION OF GENERAL ANESTHESIA
General anesthesia may be defined in different ways, but from a practical standpoint it is a pharmacologically induced physiological state involving unconsciousness, amnesia and immobility in response to noxious stimulation. Antognini et al. 2 explicitly exclude analgesia as absolute need during general anesthesia since anesthetized patients are unconscious, thus unable to perceive pain. However, analgesia is a critical anesthetic component in seldom cases when patients should recover consciousness during surgery and have recall of such experience.
The term general anesthetics should only be applied to those drugs able to induce general anesthesia. The terms "complete" and "total" may be used to show that these drugs may produce all essential components of general anesthesia and may be used as single drug for surgical anesthesia. "Incomplete" or "nonimmobilizing" anesthetics are drugs with physico-chemical characteristics similar to general anesthetics but which do not have immobilizing action 6.
This way, immobility, defined as lack of conscious movements in response to surgical noxious stimulation, is an essential component of general anesthesia produced by general anesthetics actions on CNS 8.
RELATIONSHIP BETWEEN IMMOBILITY AND MAC
MAC describes the anesthetic alveolar concentration necessary to prevent motor response to standard noxious stimulations in 50% of individuals 30. In equilibrium, partial pressures of a gas are the same in all body compartments. Since anesthetic effect depends on its concentration at the site of action, Eger et al. 30 have used alveolar concentration to define MAC, assuming that it reflects an equilibrium between lungs and blood.
The development of a reference for anesthetic potency, defined as MAC, has helped the comparison of inhalational anesthetics and has worked as a standard for relevant anesthetic concentrations in proposed anesthetic mechanisms. Since MAC is defined as loss of motor response, this anesthetic action has been sometimes confused with antinociception or analgesia. However, antinociception and immobility are probably different from each other.
Nociceptive reflexes are a protective mechanism which withdrawal the body or part of it, after noxious stimulation. These reflexes are also involved in the triggering of more complex behavioral responses to escape or face a hostile environment. All these motor responses are abolished by inhalational anesthetics to promote immobility.
Peripheral nociceptors are activated by noxious stimulations and transmit impulses to second order neurons in SC posterior horn. Second-order neurons may directly or indirectly synapse with motor neurons via higher-order interneurons. Motor neurons activation leads to muscle contraction which, depending on stimulation intensity and pattern, results in nociceptive reflex (Figure 1).
For more than one century, two concepts have dominated the reasoning about anesthetic mechanisms - the unitary hypothesis and the Meyer-Overton's lipid solubility theory 31. Unitary hypothesis claimed that all anesthetics act through a common mechanism. Campagna et al. 31, have stressed in their review the correlation described by Meyer and Overton between anesthetic potency and solubility in olive oil. These two ideas have led to the theory that volatile anesthetics would unspecifically act on cell fatty components. Most investigators have abandoned this theory because anesthetics cause just minor lipid disorders and these membrane changes may also be reproduced by minor temperature changes that do not affect behavior in animal models 32.
Well before Meyer and Overton's studies, motor activity of different animals had already been used to study anesthesia. The understanding of the anesthetic state was obtained from the observation of reflex motor behavior of such animals 29. Similarly, the concept of Eger et al. 30 about Minimum Alveolar Concentration (MAC) uses motor reflex as a measure of general anesthesia.
EVOLUTION OF THE UNDERSTANDING OF MECHANISMS OF ACTION OF INHALATIONAL ANESTHETICS
The understanding of how inhalational anesthetics act on CNS to promote immobility has greatly evolved in the last two decades. However, in spite of the widespread and safe use of inhalational anesthetics, exact sites and mechanisms of action are still unknown. Attempts to define a single mechanism of action for different anesthetic drugs have failed and today it is admitted that agent-specific effects are based on their action on specific neuronal areas.
Behavioral studies have revealed many exceptions to Meyer-Overton's lipid solubility theory and the unitary hypothesis 6. The so-called nonimmobilizers, volatile halogenate alkanes with structures similar to volatile anesthetics, would be potent anesthetics according to Meyer-Overton's lipid solubility theory. However, these compounds have no immobilizing action and may even cause seizures 6. Because volatile nonimmobilizers induce amnesia in animals 5, it is possible that immobility and amnesia are mediated by separate mechanisms 8.
Knowing that amnesia is an anesthetic effect on brain structures, new studies have concentrated in the hypothesis that SC would be the preferential site of action for inhalational anesthetics to promote immobility 33.
SPINAL CORD AS PRIMARY MEDIATOR OF IMMOBILITY
It has been assumed for a long time that immobility, together with other anesthetic components, was due to anesthetic action on the brain 34.
Initially there was the concept that motor responses were controlled by major motor neurons in the motor cortex, and that immobility would reflect anesthetic action on the cerebral cortex. However, in the early 90s, studies have shown that the SC is a major anesthetic site of action, being CSN the major site to determine inhalational anesthetics MAC.
Rampil et al. have shown that MAC has remained unchanged after pre-collicular decerebration 12 and SC hypothermal transection in rats (a technique which prevents loss of reflexes and spinal shock) 11. Antognini and Schwartz 13 have used a goat model to investigate the relative role of brain and spinal cord on anesthetic actions. Due to goats' encephalic circulation uniqueness and through a circulatory bypass unit, the brain could be selectively perfused in situ and separated from normal circulation, allowing the preferential administration of volatile anesthetics to the brain and brainstem or SC 35.
Isoflurane MAC in goats with intact native circulation was 1.2% 13. However, when SC anesthetic concentration was maintained low (0.2% to 0.3%), the brain isoflurane concentration to suppress movements was approximately 3% 13. These results indicate that inhalational anesthetics must primarily act on SC to promote immobility and that just a minor component of such immobility results from brain effects.
In a different study, also using a model of preferential isoflurane administration to brain and SC of goats, when brain isoflurane concentration was decreased to 0.3%, SC isoflurane needs were decreased (0.8% MAC) 9. This result confirms the finding that spinal cord is the primary CNS site for inhalational anesthetic immobilizing action, as opposed to Antognini and Schwartz 13, who needed major increase in brain isoflurane concentration when just 0.3% isoflurane was administered to SC. There has been a proportionally lower decrease in isoflurane MAC with the administration of similar isoflurane concentration to the brain. On the other hand, this study also suggests that, notwithstanding the spinal cord being the primary site of action to suppress movements, the brain may influence anesthetic needs by a descending inhibitory effect on SC.
Another interesting study has shown the role of brain in affecting SC excitatory and inhibitory balance. In this study, selective brain administration of high isoflurane concentrations (6% to 10%) has promoted spontaneous movements 10. It is likely that the brain affects SC excitatory and inhibitory balance, and that descending excitatory and inhibitory pathways may have different sensitivity to anesthetics.
There are still other evidences of the SC mediator role on immobility induced by volatile anesthetics. Studies have shown that anesthetic depth evaluation by brain activity monitors, either cortical through EEG and BIS 3,4,36, or subcortical through auditory evoked potential 36,37, has failed in anticipating motor response to noxious stimulation. These studies have confirmed that the brain plays a minor role in immobility and that SC is the primary anesthetic site of action to suppress somatic responses to painful stimulations. Other evidences appeared with the discovery of non-immobilizing agents, able to promote amnesia, a known brain effect of anesthetics, without promoting immobility 5-8.
INFLUENCE OF SPINAL CORD ON THE BRAIN
While studies have shown the importance of spinal cord for motor response, brain is certainly the site of action of inhalational anesthetics to promote amnesia and unconsciousness during general anesthesia. However, anesthetic action in the SC may indirectly affect brain effects of general anesthesia. It is possible that while descending signals change inhalational anesthetics immobilizing action on SC, ascending signals coming from SC also affect hypnotic actions on supraspinal centers.
Spinal and epidural anesthesia decrease the dose of sedatives needed to reach a certain sedation level, probably by blocking afferent impulses to the brain and readjusting emergence time 38. Painful stimulation during previously adequate anesthesia, results in increased neuronal activity in reticular formation and EEG desynchronization, indicating a shift toward emergence 39. Volatile anesthetics block spinal cord noxious impulses decreasing ascending transmission of painful information, which would stimulate emergence 14,40-42. The final result would be an effect on patient's state of alertness, affecting the level of consciousness and amnesia during anesthesia.
Reticular formation, thalamus and cortex are major structures for consciousness. When isoflurane is selectively administered to brain, noxious stimulations increase neuronal activity in reticular formation and thalamus and desynchronize EEG. Conversely, selective anesthetic administration to SC slows down cortical EEG signals, while gradual isoflurane concentration decrease in SC is associated to an increase in reticular formation neuron responses to painful stimulation 42. These results reaffirm the role of spinal cord in regulating supraspinal activity by modulating ascending noxious stimulations.
CELL TARGETS FOR ANESTHETIC ACTION TO PROMOTE IMMOBILITY
Peripheral axons and neuromuscular junction are unlikely to be involved in inhalational anesthetics action to promote immobility 43,44. Axonal conduction of action potentials does not seem to be affected by inhalational anesthetics in concentrations close to MAC. Supraclinical doses are needed to produce such effects as compared to those needed to affect synaptic transmission 45. Jong and Nace 46, in 1967, studied the effects of ether, methoxyflurane, halothane and nitrous oxide on saphenous nerve action potential after electric femoral nerve stimulation. In clinical concentrations, those anesthetics have not significantly affected peripheral nerve conduction or the generation of impulses in cutaneous receptors.
Spinal reflexes latency and muscle contraction were not changed after exposure to isoflurane, suggesting that this agent does not depress axonal conduction or neuromuscular transmission 27,28,44,47. However in vitro, some anesthetics seem to sensitize cutaneous nociceptors linked to Ad and C fibers 48. These excitatory effects on peripheral nociceptors, however, do not explain the suppressive action of inhalational anesthetics on CNS neurons. In a study in dogs, where authors determined isoflurane MAC by applying noxious stimulation to the tail, isolated perfusion of hind legs and tail, allowing the selective decrease of anesthetic concentration, has shown that MAC is independent of isoflurane peripheral action 49.
There are strong evidences of the presence of multiple spinal cord targets. Spinal components, that can contribute to immobility include central terminations of primary sensory afferent neurons, several interneurons and cell bodies, and proximal segments of motoneuron axons.
Spinal cord posterior horn is a possible anesthetic site of action since it is involved in nociceptive information transmission and modulation. Through a preparation in goats, in which circulation, and then anesthetic supply to the brain and SC was separated 35, selective administration of isoflurane to the spinal cord had a direct depressing effect on nociceptive responses of SC dorsal column neurons 20. On the other hand, this was not seen when the anesthetic was selectively administered to brain circulation 20. It has been experimentally shown that inhalational anesthetics suppress impulse transmission and depress SC posterior horn neuronal activity in response to noxious stimulation 15-19.
There are several in vivo studies showing inhalational anesthetics depressing action on SC dorsal column interneurons 20-23. However, nociceptive response suppression is incomplete. Antognini et al. 21 studied the depressing effects of isoflurane on spinal cord posterior horn neuron responses during administration within a narrow concentration range above and below MAC (0.9 to 1.1 MAC).
The authors observed that increased isoflurane concentration from 0.9 to 1.1 MAC, although promoting immobility, resulted in mild depression (15%) of SC posterior horn cells evoked responses. It is not clear, if such minor changes in cell activity of spinal cord posterior horn would totally justify the immobility effect induced by the drug. It is more likely that immobility is linked to suppressive activity on other sites, in addition to SC posterior horn neurons. Possible mechanisms could include direct action on SC anterior horn motor neurons and supraspinal modulating influences. Supraspinal modulating effect has been suggested in goats in which, during low isoflurane concentrations administration to SC, progressive brain isoflurane concentrations decrease has promoted increased SC posterior horn nociceptive responses 50.
Recent studies have suggested that surgical immobility is promoted by anesthetic suppression of spinal cord motor neurons 25-28. Anesthetic effect on motor pathways can be studied through electrophysiological methods such as motor evoked potential 47, Hoffmann's reflex (H-reflex) 27,28.51 and F-wave 25-28,47,52,53.
Motor evoked potential is produced by transcranial magnetic stimulation on the motor cortex and is captured by electrodes placed on the muscle where motor activity is to be assessed. Motor evoked potential evaluates the functional integrity of the whole motor pathway.
Spinal motor neurons excitability may be noninvasively evaluated through Hoffmann's reflex (H-reflex) and F-wave. H-reflex is a monosynaptic effect produced by electrical stimulation of a mixed peripheral nerve 54. Reflex is mediated by large sensory (Ia) and motor (Aa) fibers, typically containing a centrally amplified H wave which is larger than the associated M wave 54,55. Clinically, H-reflex is affected by spinal motor neurons excitability and sensory neurons responsiveness, thus suffering supraspinal modulation 55. H-reflex changes are nonspecific since general anesthesia may suppress the reflex by decreasing motoneuron excitability, sensory neuron responsiveness or synaptic transmission.
F-waves are recurrent evoked electromyographic signals 56. As opposed to H-reflex, F-wave is not a reflex. It is a delayed muscle potential evoked by supramaximal electric stimulation of a peripheral nerve. Afferent and efferent pathways are of the same alpha motor neuron. F-wave represents antidromic invasion of central motor neurons which are depolarized triggering orthodromic impulses after the absolute refractory period 56,57 (Figure 2). In addition to representing spinal motor neuron intrinsic excitability, F-wave also reflects excitatory and inhibitory influences on motor neurons.
F-wave amplitude is related to the size and number of activated motor units, that is it reflects motor neurons excitability 58. F-wave persistence indicates antidromic excitability of a group of motor neurons 57. So, suppression of F-wave amplitude and persistence suggests decreased motor neurons excitability.
Inhalational anesthetics depress H-reflex and F-wave amplitude in concentrations that inhibit motor responses to noxious stimulations 25-28,47,52,53. F-wave depression by volatile anesthetics is dose-dependent and closely related to suppression of movement in response to noxious stimulation (MAC) 25-28,52 (Figure 3). In rats, F-wave suppression by isoflurane and nitrous oxide was correlated to depression of motor response to tail clamping 52. In humans, isoflurane, with or without nitrous oxide, decreased H-reflex and F-wave amplitude and persistence 27. These findings suggest that the decrease of motor neuron excitability can play a major role in anesthetic-induced immobility. However, differences were identified among agents regarding their effects on F-wave, enflurane significantly greater depression than sevoflurane, desflurane and halothane in concentrations above 1 MAC.
It is not clear, however, whether motor neuron excitability depression is due to a direct action of inhalational anesthetics on spinal cord, or if there is also an indirect brain effect transmitted to SC. Some studies have shown that F-wave depression seems to represent a direct action on spinal motor neurons with minor or none indirect supraspinal component 53.
Motor evoked potentials are virtually abolished by low isoflurane concentrations (0.5%) 47, but F-waves, although depressed, are still present 47. This suggests that spinal motor neuron excitability is independent of upper motor neuron action. Almost total F-wave depression with 0.8% spinal concentration, regardless of brain concentration, also suggests that anesthetic effects on motor neuron excitability is not an indirect supraspinal action 53. However, a previous study has shown that the cortex is able to modulate spinal motor neuron excitability through post-synaptic effects 59.
In addition, it is unlikely that spinal motor neuron excitability suppression is the single mechanism involved with immobility since selective SC administration of isoflurane concentrations below MAC (0.8%) virtually abolishes F-wave, but still allows for the presence of movements 53. The combination of 0.3% brain and 0.8% spinal isoflurane concentrations is enough to prevent movements in response to noxious stimulations in 50% of animals (MAC) 9. This low brain isoflurane concentration would hypothetically have more pronounced effects on descending supraspinal excitation than on inhibition, thus favoring immobility.
MOLECULAR ACTIONS OF INHALATIONAL ANESTHETICS TO PROMOTE IMMOBILITY
It is possible that a wide variety of neurotransmitter systems are affected by inhalational anesthetics, but how these actions are translated into anesthesia is still unknown. So, it is very difficult to associate inhalational anesthetic effects on specific ionic channels to behavioral effects of anesthesia. Studies evaluating pre and post-synaptic effects of inhalational anesthetics have shown actions both on neurotransmitters release and related receptors functions 60.
In vitro and in vivo studies have shown that a large number of ion channels modulating cell electric activity are associated to anesthetics behavioral and physiological actions 61. In synapses, ion channels may influence presynaptic release of neurotransmitters and change post-synaptic excitability. Some channels are sensitive to clinically effective concentrations of several inhalational anesthetics, indicating that they are possible targets for anesthetic action 61.
Genetic studies have observed the effect of receptor mutations (elimination or change) on MAC. Pharmacological studies evaluate the effect of specific ion channel agonists and antagonists on MAC and add to the knowledge obtained with genetic studies by revealing the importance of ion channels candidate to mediate MAC. When different mutations and drugs show the same response pattern, the consistency of results reinforces conclusions about the relevance of the receptor under evaluation.
The comparison of anesthetic effects and non-immobilizing drugs may also be used to test the importance of a certain ion channel. Although 1-chlorine-1,2,2-trifluorocyclobutane (called F3) and nonimmobilizer F6 are structurally similar, with liposolubility compatible with anesthetic properties, only F3 affects the function of GABAA, glycine, AMPA, kainate, and 5-HT3 receptors, indicating that these receptors may be involved with inhalational anesthetics-induced immobility 62. In contrast, both F3 and F6 are able to inhibit nicotinic receptors and several metabotropic receptors, so these receptors should not be involved with anesthetic-mediated immobility 63.
A compilation of pharmacological and genetic in vivo and in vitro studies has evaluated the role of different neurotransmitters, ion channels and metabotropic receptors. Molecular areas may be classified according to their relevance as direct mediators of immobility.
Relevant Mediators of Immobility
The joint evaluation of in vitro and in vivo studies grants to glycine receptors a relevant role in mediating immobility promoted by inhalational anesthetics. Glycine receptors are the primary sites of SC inhibitory neurotransmission. They are major candidates to MAC mediators due to their spinal location and potentiation by inhalational anesthetics 64.
In clinically relevant concentrations, halothane, isoflurane and enflurane prolong post-synaptic glycinergic current duration, but do not increase its amplitude 65. In intact preparations, anesthetics do not promote absolute increase of inhibition. So, anesthetics affect inhibition duration but not the magnitude of glycinergic transmission, increasing the period in which it is effective.
In vitro effects of inhalational anesthetics on glycine receptors correlate to in vivo studies in which glycine antagonists increased inhalational anesthetics MAC. Intravenous and spinal strychnine administration in animals increases MAC 66,67. Correlation between this effect on MAC and in vitro results indicates that glycine receptor is partially responsible for volatile anesthetics immobilizing effects 67.
Probably Relevant Mediators
Some neurotransmitters and receptors could play a relevant role in mediating immobility. Although recent knowledge points to a direct effect on these molecules, some contradictory results do not allow us to state that inhalational anesthetics really have a direct action on such neurotransmitter systems and ion channels to induce immobility.
Glutamate is the major excitatory neurotransmitter in mammalian CNS. In preparations of spinal cord segments, volatile anesthetics depress excitatory currents evoked by glutamate administration to motor neurons 68. In addition, volatile anesthetics depress currents generated by AMPA and NMDA receptors through actions independent from GABAA and glycine receptors, suggesting that efferent motor activity inhibition results both from depression of excitation and increase of inhibition 68.
Several results suggest potential importance of NMDA receptors as mediators of inhalational anesthetics immobilizing effect.
In vitro, ether, chloroform, methoxyflurane, halothane, enflurane and isoflurane decrease NMDA receptor activity 69. Recombinant NMDA receptors are also depressed by clinically relevant isoflurane, sevoflurane and desflurane concentrations, in a reversible and dose-dependent way 70.
Some studies, however, have suggested a possible supraspinal effect on spinal NMDA receptors activity. Masaki et al. 71 have shown sevoflurane MAC decrease after brain intraventricular administration of D-AP5 (NMDA antagonist), while Ishizaki et al. 72 have found a maximum 30% decrease in isoflurane MAC in rats after spinal administration of AP5, MK-801, CPP and 7CKA (NMDA antagonists).
These results have then suggested a predominantly supraspinal effect of inhalational anesthetics on NMDA receptors. Conversely, MK-801 in rats has decreased isoflurane MAC. MAC decrease was primarily correlated to the concentration of antagonist in the spinal cord instead of its brain or cortical concentration. This result is consistent with the mediator role of spinal cord NMDA receptor to promote immobility 73.
Another finding was the persistence of temporal summation during anesthesia with isoflurane. Conversely, temporal summation is eliminated by NMDA blockade 74 and anesthesia with xenon, indicating different mechanisms of action between anesthetic drugs.
Recent data have shown that pre-synaptic sodium channels inhibition can block neurotransmitters release, especially glutamate 75. Different volatile anesthetics inhibit pre-synaptic sodium channels 76,77, while nonimmobilizers are unable to do it 78. So, sodium channels might be relevant targets for anesthetic action.
5-HT2A receptors participate of nociception. Inhalational anesthetics may block in vitro the effect of 5-HT on 5-HT2A receptors in concentrations close to 1 MAC 63. Doherty et al. 79 observed that R51703 antagonist decreases halothane MAC in dogs. Similarly, Zhang et al. 75 found a maximum 60% decrease in isoflurane MAC in rats. These data are consistent with the hypothesis that 5-HT2A receptors could directly mediate a minor component of inhalational anesthetics induced immobility. However, there is one in vitro finding that 5-HT2A receptor is equally affected by both halothane and the nonimmobilizer F6 63.
Possibly Irrelevant Mediators
Potassium channels are feasible candidates to mediators of immobility because they are numerous, diverse, and increase potassium conductance decreasing nervous system excitability. However, there is no current evidence showing that potassium channels are mediators of immobility. Intravenous administration of the activator riluzole has the same effect on MAC as its spinal administration. On the other hand, their great number and diversity prevent a final conclusion on their role.
Glutamate AMPA receptors act on fast post-synaptic excitatory transmission component and could be feasible targets for inalational anesthetics action. In fact, competitive intravenous 80 or spinal 81 antagonists largely decrease halothane and isoflurane MAC. Electrophysiological in vitro studies have shown that inhalational anesthetics depress post-synaptic excitatory currents mediated by AMPA receptors 68.
However, genetically modified rats have supplied major information on the role of AMPA receptors inhibition upon inhalational anesthetics actions. Rats lacking the GluR2 subunit were more sensitive to halothane, sevoflurane and isoflurane than rats with no genetic modification in terms of loss of righting reflex and antinociception, but not in terms of immobility (MAC) 82.
Clinical concentrations of halothane and isoflurane have minimally inhibited AMPA receptor in producing immobility, both in rats with no genetic modification and GluR2 subunit deficient rats82. So, studies with GluR2 subunit deficient rats support the idea that different neuronal circuits are mediators of MAC, antinociception and righting reflex. Although in vivo data suggest that the lack of GluR2 subunit does not affect MAC, the possibility of other AMPA receptor subunits contributing to MAC cannot be ruled out.
Probably Irrelevant Mediators
Some neurotransmitter systems are unlikely to play a direct role on inhalational anesthetics immobilizing effect. Inconsistent results of in vivo and in vitro studies, however, could not show a role of these neurotransmitter systems in promoting immobility.
GABAA are the most abundant brain inhibitory receptors. In clinical concentrations, inhalational anesthetics increase in vivo GABA receptor sensitivity and prolong inhibitory currents after neurotransmitter binding. The end result is increased post-synaptic inhibition contributing to anesthetic depressing actions 83. In the intact spinal cord, GABAA receptors blockade decreases depressor effects of anesthetics 84.
However, GABAA receptors modulation alone is not enough to explain the effect of all inhalational anesthetics. Although many inhalational anesthetics increase GABA action in vitro, and studies in rats with genetically modified GABAA receptors indicate that these could mediate immobility, in vivo studies have not indicated that these receptors are responsible for inhalational anesthetics-induced immobility.
Xenon and nitrous oxide virtually do not increase GABA actions in vitro 85. Conversely, these gases inhibit glutamate NMDA receptors and acetylcholine nicotinic receptors, suggesting that excitatory channels are alternative anesthetic pathways. In rats, picrotoxine, non-competitive GABAA antagonist, increased ketamine and isoflurane immobilizing dose up to a ceiling effect of 60% 86. Since ketamine does not act on GABAA receptors, this finding was probably the result of antagonism of GABA natural release effect. Conversely, picrotoxin has increased propofol ED50 in approximately 400% without ceiling effect, reflecting direct antagonism. These findings suggest that isoflurane immobilizing effect is not directly mediated by GABAA receptors. Similar conclusions were drawn after picrotoxin administration in rats inhaling isoflurane, xenon or cyclopropane. MAC has equally increased for all anesthetics indicating that GABAA receptors are not more important for isoflurane immobilizing action than for anesthetics with minor effects on GABAA receptors.
Although GABAA receptors are unlike mediators of immobility, a final conclusion would require the development of genetically modified rats with GABAA receptors normally responding to GABA, but which are not potentiated by inhalational anesthetics 29.
5-HT3 receptor is considerably similar to GABAA, glycine and nicotinic cholinergic receptors. Therefore, some inhalational anesthetics potentiate 5-HT3 receptor response 87. This pro-excitatory in vitro effect suggests that 5-HT3 receptors do not interfere with immobility. Confirming this conclusion, studies in rats have shown that 5-HT3 receptors blockade by systemic or spinal ondansetron does not affect the MAC of isoflurane 88.
Acetylcholine receptors are also affected by volatile anesthetics. However, although able to deeply affect neuronal transmission, nicotinic and muscarinic receptors blockade did not change anesthetic potency, both in vitro and in vivo, and should not be important to promote immobility 89,90. The administration of a nicotinic antagonist (mecamylamine) to rats did not decreased motor responses after nociceptive stimulation 89,90. Similarly, nicotine agonist administration did not change the MAC of isoflurane 89. Finally, nonimmobilizers also inhibit acetylcholine nicotinic receptors, suggesting that these receptors are not responsible for inhalational anesthetics-induced immobility.
Opioid receptors have also no direct importance on inhalational anesthetics immobilizing action, since inhalational anesthetics do not increase endogenous CSF opioids and high naloxone doses in rats have no effects on halothane 91 and nitrous oxide 92 MAC.
Alpha2-adrenergic antagonists decrease inhalational anesthetic MAC in animals 93 and humans 94, but it is possible that a2-adrenergic receptors are irrelevant for MAC. Alpha2-adrenergic receptors depletion does not change halothane MAC in rats 95 and ioimbine and atypamezol (a-adrenergic blockers) increase isoflurane MAC in just approximately 10%, reaching a ceiling effect and not indicating a direct role of these receptors in mediating immobility 96.
There are currently no objective criteria to quantify all clinical components of modern general anesthetic drugs, such as immobility, hypnosis and suppression of hemodynamic responses to noxious stimulations. Concentration of each drug should be titrated and different functional variables should be independently and simultaneously monitored to assure that therapeutic objectives of anesthesia are reached.
If sites and mechanisms of action to suppress movement were known, and a specific anesthetic drug was developed, significantly lower concentrations would be needed to produce other anesthetic components (amnesia and unconsciousness) since anesthetic dose enough to produce them is significantly lower than that needed to suppress movement.
The understanding of mechanisms through which inhalational anesthetics act to promote immobility has greately progressed in the last two decades. Today it is known that SC is the primary site of action for anesthetics in the CNS to promote immobility during general anesthesia. However, there is no single anesthetic action target. Spinal nociceptive neurons and motor neurons are differently affected by volatile anesthetics. Similarly, several receptors - metabotropic and coupled to ion channels - have their function modified by inhalational anesthetics, but not all of them are directly involved with inhalational anesthetics immobilizing action.
Mollecular, neurophysiologic and behavioral investigations support a role for glycine 5-HT3 receptors and NMDA receptors. However, voltage-dependent sodium channels blockade by inhalational anesthetics and increased potassium channels function should not be ruled out as possible mechanisms. On the other hand, other members of the superfamily of ligand-mediated ion channels (GABAA, nicotinic cholinergic and 5-HT3) are unlikely to interfere with immobility promoted by inhalational anesthetics in spite of the evidences thatGABAA receptors are responsible for immobility promoted by some intravenous anesthetics.
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Dr. Leonardo Teixeira Domingues Duarte
Address: SQSW 306, Bloco E Aptº 304 Setor Sudoeste
ZIP: 70673-435 City: Brasília, Brazil
Submitted for publication April 23, 2004
Accepted for publication October 13, 2004
* Received from Rede Sarah de Hospitais do Aparelho Locomotor, Brasília, DF