G. POCOCK AND C. D. RICHARDS. The administration of inhalation anaesthetic
agents is followed by a series of behavioural changes that were first described ...
British Journal of Anaesthesia 1993; 71: 134-147
EXCITATORY AND INHIBITORY SYNAPTIC MECHANISMS IN ANAESTHESIA G. POCOCK AND C. D. RICHARDS
The administration of inhalation anaesthetic agents is followed by a series of behavioural changes that were first described systematically by Guedel for diethyl ether [49]. The patient passes through stages of analgesia and delirium to reach the unconsciousness of the lighter planes of surgical anaesthesia. The precise pattern of behavioural change varies from agent to agent, and this has caused a great deal of confusion regarding the precise definition of general anaesthesia. In essence, we administer general anaesthetics during surgery to block both the perception of stimuli, particularly painful stimuli, and the accompanying reflex motor responses. General anaesthesia is therefore characterized by loss of consciousness and reduction in reflex activity. As the functional unit of reflex activity is the neurone and as the overall pattern of nervous activity is governed by the functional connections between neurones, we may assume that anaesthetics act by modulating information processing in neural networks. This review is concerned with the mechanisms that underpin this modulation and updates an earlier article on the same subject [109]. In the early part of this century, Sherrington [132] stressed the importance of the synapse in CNS processing. Since then, the details of synaptic transmission within the CNS have gradually been unravelled. The principal events may be summarized as follows: a nerve cell receives information by way of synaptic contacts all over the dendrites and cell body. Impulses travelling in the presynaptic fibres invade the terminal branches to depolarize the nerve endings. This depolarization leads to the opening of the voltage-gated calcium channels and an influx of calcium into the terminal. The subsequent increase in intracellular calcium is the trigger for the exocytotic secretion of transmitter substance from the nerve terminal. The released transmitter diffuses across the synaptic cleft and binds to specific receptor sites on the postsynaptic membrane. Activation of the receptors results in a change in the permeability of the membrane to particular ions, which in turn
leads to a change in membrane potential and to excitation or inhibition of the next neurone of the network, depending on the nature of the synapse under investigation. This brief outline describes the classical view of synaptic transmission as a mediator of fast events, such as spinal reflexes. Receptors linked directly to ion channels are adapted to fast signalling, but it is now known that synaptic contacts may exert a more subtle long-term modulation of excitability. This modulation operates generally via second messengers such as cAMP and IP3. For example, noradrenaline interacts with two different classes of receptor, one class activates adenylate cyclase (beta adrenoceptors) and the other inhibits adenylate cyclase (alpha adrenoceptors) [106]. Similarly, the response of muscarinic acetylcholine receptors depends upon the receptor subtype. Ml, M3 and M5 receptors activate phospholipase C and generate diacylglycerol and inositol triphosphate (IP3) while M2 and M4 receptor activation is associated with inhibition of adenylate cyclase [40]. Many other CNS transmitters (e.g. dopamine, substance P, 5-HT) are now thought to activate second messenger systems. Nevertheless, both fast and slow synaptic events ultimately modulate specific ion channels and alter the level of excitability of the postsynaptic neurones. The resulting pattern of action potentials encodes information for transmission to the other neurones in the network via other synaptic contacts. Nerve terminals themselves are subject to modulation by presynaptic axonal contacts via presynaptic inhibition [129]. Moreover, axons branch during their course and the spatial pattern of impulses is subject to modulation as changes in threshold at branch points may result in different patterns of impulse activity in different nerve branches. As with alterations to the temporal pattern of activity, changes in the spatial pattern of activity has consequences for information processing by the CNS [113]. The schematic drawing in figure 1 outlines the principal anatomical features that underpin neural processing. After the early studies of Sowton and Sherrington [139], several workers investigated the actions of anaesthetics on synaptic transmission in die spinal
(Br. J. Anaesth. 1993; 71 : 134-147) KEY WORDS General anaesthesia • neurotransmitters, synapses. Mechanism of action. Membrane excitability.
Downloaded from https://academic.oup.com/bja/article-abstract/71/1/134/303899 by guest on 06 November 2017
G. POCOCK, PH.D., C. D. RICHARDS, PH.D., Department of Physi-
ology, Royal Free Hospital School of Medicine, Rowland Hill Street, London NW3 2PF. Correspondence to C.DR.
EXCITATORY AND INHIBITORY SYNAPTIC MECHANISMS IN ANAESTHESIA Presynaptic inhibitory axon Afferent axon
135
on fast synaptic transmission as this area has received most experimental study. ACTIONS OF ANAESTHETICS ON EXCITATORY SYNAPTIC TRANSMISSION
Terminal arborization
Impulse propagation Excitatory synapses
Inhibitory synapse Cell b o d y
v ^ / -
x
//-inhibitory interneurone
Axon co lateral FIG. 1. Schematic diagram of the organization of a synaptic relay within the CNS.
cord and brain. General anaesthetics have been found to depress excitatory synaptic transmission at concentrations likely to be found in the brain during surgical anaesthesia [16, 70, 115, 121, 123, 135, 136, 152]. The effects of anaesthetics on inhibitory synaptic transmission are more varied, as both depression [34, 39, 88, 133] and enhancement [7, 34, 92, 94, 95, 130, 131] have been reported. From this brief outline of synaptic processing, it is clear that anaesthetics may act at a number of different sites. To reduce transmission through a synaptic relay, anaesthetics may either depress excitation or enhance inhibition. Excitation may be depressed in several ways: by block of action potential propagation, by enhancing presynaptic inhibition, by depressing the release of excitatory transmitters or by depressing the response of the postsynaptic receptors. Anaesthetics may enhance postsynaptic inhibition by increasing the release of inhibitory neurotransmitters or by augmenting the response of postsynaptic receptors. Modulation of synaptic activity results in a change in information processing in the brain. In addition, it is possible that anaesthetics may act directly on postsynaptic neurones by modulating excitability. This could be achieved by increasing directly the threshold for action potential discharge. Alternatively, anaesthetics may modulate the resting conductance of the postsynaptic membrane and so change the membrane potential. Finally, anaesthetics may modulate patterns of action potential discharge, either at the point of initiation or at axon branch points. To determine precisely how anaesthetics affect information processing in the CNS, we need to investigate systematically the action of anaesthetics on each of the processes mentioned above. We will be concerned chiefly with two questions: (1) What changes in information processing occur during anaesthesia? (2) What cellular and molecular mechanisms are responsible for these changes ? We will focus mainly on the action of anaesthetics
Downloaded from https://academic.oup.com/bja/article-abstract/71/1/134/303899 by guest on 06 November 2017
Do anaesthetics depress excitatory synaptic transmission by block of impulse conduction in the presynaptic nerve fibres? The early studies of Bremer and Bonnet [13, 16] and Larrabee and Posternak [70] showed that impulse conduction in axons was unaffected largely by a variety of anaesthetic agents at concentrations ordinarily required for surgical anaesthesia. Synaptic events, however, were decreased significantly by concentrations of anaesthetics within the clinically relevant range. As Larrabee and Posternak have shown, however, these events were only 5—10 times more sensitive to inhibition than impulse conduction. Thus in comparison with very specific blockers of synaptic transmission, such as atropine, curare or propranolol, anaesthetics are not very selective inhibitors of synaptic activity. More recent work by Somjen [135, 136], Weakly [152] and Richards and coworkers [115, 117, 118, 121, 123, 124] has confirmed that synaptic transmission in the CNS is significantly more sensitive to depression by most anaesthetic agents than is action potential propagation. Although this evidence suggests strongly that a decrease in action potential propagation is unlikely to occur in nerve trunks during general anaesthesia, some workers have suggested that a reduction in action potential amplitude in nerve terminals may lead to a decrease in excitatory synaptic transmission [9,36]. If this were so, in carefully chosen experimental situations it should be possible to mimic the effects of general anaesthetics by the application of nerve blocking agents, such as procaine or tetrodotoxin. Detailed examination of the synaptic potentials evoked by electrical stimulation of afferent pathways in the olfactory cortex and hippocampus has shown that a wide variety of general anaesthetics depress excitatory synaptic transmission with no significant change, either in the amplitude of the focally recorded action potential or in the latency of onset of the excitatory postsynaptic potentials (EPSPS) [9,115,117,121,124]. Similar experiments performed with nerve blocking agents show changes in both, as expected [118] (seefig.2). At large concentrations of anaesthetic, such as those experienced briefly during induction of general anaesthesia, propagation of impulses may be impaired, especially at points with small safety factors, such as fine axon branches. Evidence that this may occur has recently come from work by Berg-Johnsen and Langmoen [9] who found that impulse conduction in the small unmyelinated fibres (0.1-0.2 \im diameter) of the rat hippocampus was far more sensitive to block by isoflurane than impulse conduction in the myelinated fibres of the fimbria (1 nm diameter). If such a block were to occur at small concentrations of other anaesthetics, it would contribute to depression of excitatory synaptic transmission. Although this does not appear to be the case
BRITISH JOURNAL OF ANAESTHESIA
136
0
10
20
30
40
50
60
70
80
1-6-1
i.o H 2.0 -i
>
-.
- 1.75
_
-1.5
|
-
-
-1.0
V ' xx'"S.x
< o
-0.75
x\
Q. LLJ
1 25
*xx „ « " "
o Q.
o
