Immobility: essential inhalational anesthetics action

Abstracts

JUSTIFICATIVA E OBJETIVOS: A imobilidade é uma característica essencial da anestesia geral e que deve ser buscada e mantida durante todo o ato anestésico. A potência anestésica, chamada Concentração Alveolar Mínima (CAM), é a expressão da inibição dos movimentos em resposta a estímulos nociceptivos. Entretanto, apesar da medula espinhal ser reconhecida como principal mediadora da imobilidade cirúrgica, os mecanismos celulares e subcelulares da ação dos anestésicos inalatórios para produzirem imobilidade não são, ainda, totalmente conhecidos. Tendo em vista o grande avanço na pesquisa dos mecanismos de ação dos anestésicos inalatórios e a resultante grande quantidade de informações, essa revisão tem como objetivo avaliar criticamente os estudos clínicos e experimentais realizados para identificação dos mecanismos e locais de ação dos anestésicos inalatórios para produção de imobilidade em resposta a estímulos nociceptivos. CONTEÚDO: Os mecanismos de ação dos anestésicos inalatórios no SNC podem ser divididos em três níveis: macroscópico, microscópico e molecular. No aspecto macroscópico, estudos comportamentais mostraram ser a medula espinhal o principal local da ação anestésica para promover imobilidade em resposta à estimulação dolorosa. No nível celular, a excitabilidade dos motoneurônios, neurônios nociceptivos e a transmissão sináptica estão, todos, envolvidos na ação dos anestésicos inalatórios. Sob o ponto de vista molecular, diversos receptores são afetados pelos anestésicos, mas poucos devem mediar diretamente a ação anestésica. Entre estes, destacam-se os receptores de glicina, NMDA de glutamato, 5-HT2A, e canais de sódio voltagem-dependentes. CONCLUSÕES: A imobilidade produzida pelos anestésicos inalatórios é mediada, principalmente, através de uma ação sobre a medula espinhal. Esse efeito ocorre pela ação anestésica sobre a excitabilidade dos neurônios motores espinhais, mas também sobre neurônios e interneurônios nociceptivos do corno posterior da medula. A ação sobre os receptores específicos exerce efeito sobre a transmissão sináptica desses neurônios.

ANESTESIA, Geral; MONITORIZAÇÃO

REVIEW ARTICLE

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

^{Correspondence}

SUMMARY

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-HT_2A 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

RESUMEN

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.

INTRODUCTION

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).

Brazilian Journal of Anesthesiology, 2005; 55: 1:  100 - 117

Immobility: essential inhalational anesthetics action

Leonardo Teixeira Domingues Duarte; Renato Ângelo Saraiva

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.

Brazilian Journal of Anesthesiology, 2005; 55: 1:  100 - 117

Immobility: essential inhalational anesthetics action

Leonardo Teixeira Domingues Duarte; Renato Ângelo Saraiva

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.

Brazilian Journal of Anesthesiology, 2005; 55: 1:  100 - 117

Immobility: essential inhalational anesthetics action

Leonardo Teixeira Domingues Duarte; Renato Ângelo Saraiva

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 GABA_A, 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 GABA_A 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-HT_2A receptors participate of nociception. Inhalational anesthetics may block in vitro the effect of 5-HT on 5-HT_2A 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-HT_2A receptors could directly mediate a minor component of inhalational anesthetics induced immobility. However, there is one in vitro finding that 5-HT_2A 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.

GABA_A 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, GABA_A receptors blockade decreases depressor effects of anesthetics ⁸⁴.

However, GABA_A 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 GABA_A 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 GABA_A antagonist, increased ketamine and isoflurane immobilizing dose up to a ceiling effect of 60% ⁸⁶. Since ketamine does not act on GABA_A 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 GABA_A receptors. Similar conclusions were drawn after picrotoxin administration in rats inhaling isoflurane, xenon or cyclopropane. MAC has equally increased for all anesthetics indicating that GABA_A receptors are not more important for isoflurane immobilizing action than for anesthetics with minor effects on GABA_A receptors.

Although GABA_A receptors are unlike mediators of immobility, a final conclusion would require the development of genetically modified rats with GABA_A receptors normally responding to GABA, but which are not potentiated by inhalational anesthetics ²⁹.

5-HT₃ receptor is considerably similar to GABA_A, 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.

CONCLUSION

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 (GABA_A, nicotinic cholinergic and 5-HT₃) are unlikely to interfere with immobility promoted by inhalational anesthetics in spite of the evidences thatGABA_A receptors are responsible for immobility promoted by some intravenous anesthetics.

REFERENCES

Submitted for publication April 23, 2004

Accepted for publication October 13, 2004

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*

Received from Rede Sarah de Hospitais do Aparelho Locomotor, Brasília, DF

Publication Dates

• Publication in this collection
  01 Mar 2005
• Date of issue
  Feb 2005

History

• Accepted
  13 Oct 2004
• Received
  23 Apr 2003