Anaesthetic modulation of synaptic transmission in the mammalian CNS (original) (raw)
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Effects of Anaesthetics on Uptake, Synthesis and Release of Transmitters
British Journal of Anaesthesia, 1993
While the molecular basis of the action of most anaesthetic agents is unknown, it is a commonly held view that general anaesthetic drugs have a more pronounced effect on synaptic mechanisms in the central nervous system (CNS) than on the propagation of electrical signals along axons [39]. A more contentious issue relates to whether or not anaesthetic agents act generally, producing a range of metabolic alterations which together result in anaesthesia or at, as yet, unidentified specific sites in neuronal mechanisms [25]. Sensory information is passed from cell to cell in the CNS by neurotransmitters. These transmitter substances are released in the synaptic cleft between adjacent cells and, depending on the particular synapse, can interact with presynaptic and/or postsynaptic receptors. The postsynaptic actions of transmitter substances are mediated classically via excitatory postsynaptic potentials (EPSP) or inhibitory postsynaptic potentials (IPSP) and the size of these can be modulated by the regulation of transmitter release from the nerve terminal by the interaction of neurotransmitter substances at receptors in the presynaptic membrane. The diversity of different transmitter substances and the complex interplay between transmitter systems results in a large number of potential sites of action of anaesthetic agents (fig. 1). EXPERIMENTAL SYSTEMS Although there have been a number of in vivo studies [4, 9, 55-57, 65], by far the majority of studies on the action of anaesthetic agents on transmitter systems have been carried out in in vitro preparations. Three major experimental paradigms, namely synaptosomes, brain slices and cells in culture, have been used in in vitro studies (fig. 2). Each of these systems has limitations and caution must be exercised in extrapolating conclusions from these studies to the clinical situation. Synaptosomes are pinched off nerve endings that are formed when brain tissue is homogenized. The synaptosome fraction is separated from particulate
BJA: British Journal of Anaesthesia, 1988
General anaesthetics can depress synaptic transmission and neuronal excitability in the central nervous system (CNS) [1,2]. Although it is possible that CNS depression is the major action underlying anaesthesia, evidence exists for anaesthetic-induced facilitation of excitatory transmission [3-5] and various patterns of " activated " EEG recordings have been observed during anaesthesia [6,7]. Furthermore, anaesthetics produce agent-specific effects on CNS electrical activity in vivo [8], and a single anaesthetic state, or common neurophysiological mechanism, has not been observed for all anaesthetics. Concentration-dependent and anaesthetic-specific differential effects have also been reported on a number of invertebrate and isolated mammalian peripheral nervous system preparations [9]. These differential actions do not support a traditional "unitary" theory of anaesthesia [2,8-11]; rather, actions at multiple and selective membrane sites appear likely [12-14]. Recent studies of anaesthetic actions on vertebrate CNS neurones in vitro have not revealed differences in action between agents. For example, it was reported that a number of general anaesthetics (including inhalation agents and barbiturates) hyperpolarize neurones of the spinal cord and hippocampus [1], and a good correlation
Effects of general anaesthetics on neuronal sodium and potassium channels
General pharmacology, 1992
1. The effects of clinical inhalation anaesthetics, such as halothane and methoxyflurane, and "model" anaesthetics, such as hydrocarbons and n-alkanols, on neuronal sodium and potassium channels are reviewed. 2. Lipid-based mechanisms for the actions of anaesthetics on the gating parameters of squid axon sodium and delayed rectifier potassium currents are considered in conjunction with evidence of more specific effects in other preparations, notably a fast inactivating potassium current in Helix neurones and a voltage-gated sodium current in rat dorsal root ganglion neurones. 3. The proconvulsant actions of some inhalation anaesthetics are discussed in relation to the induction of spontaneous firing of action potentials in the squid giant axon.
Brain research, 2006
Although it is evident that general anesthesia should affect impulse activity and neurochemical responses of central neurons, there are limited studies in which these parameters were compared in both awake and anesthetized animal preparations. We used single-unit recording coupled with iontophoresis to examine impulse activity and responses of substantia nigra pars reticulata (SNr) neurons to GABA, glutamate (GLU), and dopamine (DA) in rats in awake, unrestrained conditions and during chloral hydrate anesthesia. SNr neurons in both conditions had similar organization of impulse flow, but during anesthesia, they have lower mean rates and discharge variability than in awake conditions. In individual units, discharge rate in awake, quietly resting rats was almost three-fold more variable than during anesthesia. These cells in both conditions were highly sensitive to iontophoretic GABA, but the response was stronger during anesthesia. In contrast to virtually no responses to GLU in awak...
The in vivo neurochemistry of the brain during general anesthesia
Journal of neurochemistry, 2011
Anesthesia describes a complex state composed of immobility, amnesia, hypnosis (sleep or loss of consciousness), analgesia, and muscle relaxation. Bottom-up approaches explain anesthesia by an interaction of the anesthetic with receptor proteins in the brain, whereas top-down approaches consider predominantly cortical and thalamic network activity and connectivity. Both approaches have a number of explanatory gaps and as yet no unifying view has emerged. In addition to a direct interaction with primary target receptor proteins, general anesthetics have massive effects on neurotransmitter activity in the brain. They can change basal transmitter levels by interacting with neuronal activity, transmitter synthesis, release, reuptake and metabolism. By that way, they can affect a great number of neurotransmitter systems and receptors. Here, we review how different general anesthetics affect extracellular activity of neurotransmitters in the brain during induction, maintenance, and emerge...
General anaesthetic action at transmitter-gated inhibitory amino acid receptors
Trends in Pharmacological Sciences, 1999
Research within the past decade has provided compelling evidence that anaesthetics can act directly as allosteric modulators of transmitter-gated ion channels. Recent comparative studies of the effects of general anaesthetics across a structurally homologous family of inhibitory amino acid receptors that includes mammalian GABA A , glycine and Drosophila RDL GABA receptors have provided new insights into the structural basis of anaesthetic action at transmitter-gated channels. In this article, the differential effects of general anaesthetics across inhibitory amino acid receptors and the potential relevance of such actions to general anaesthesia will be discussed.
Faculty of 1000 evaluation for Sodium channels and the synaptic mechanisms of inhaled anaesthetics
F1000 - Post-publication peer review of the biomedical literature, 2009
General anaesthetics act in an agent-specific manner on synaptic transmission in the central nervous system by enhancing inhibitory transmission and reducing excitatory transmission. The synaptic mechanisms of general anaesthetics involve both presynaptic effects on transmitter release and postsynaptic effects on receptor function. The halogenated volatile anaesthetics inhibit neuronal voltage-gated Na þ channels at clinical concentrations. Reductions in neurotransmitter release by volatile anaesthetics involve inhibition of presynaptic action potentials as a result of Na þ channel blockade. Although voltage-gated ion channels have been assumed to be insensitive to general anaesthetics, it is now evident that clinical concentrations of volatile anaesthetics inhibit Na þ channels in isolated rat nerve terminals and neurons, as well as heterologously expressed mammalian Na þ channel a subunits. Voltage-gated Na þ channels have emerged as promising targets for some of the effects of the inhaled anaesthetics. Knowledge of the synaptic mechanisms of general anaesthetics is essential for optimization of anaesthetic techniques for advanced surgical procedures and for the development of improved anaesthetics.
Modulation of reconstructed peptidergic synapses and electrical synapses by general anaesthetics
Toxicology Letters, 1998
1. The actions of clinically relevant concentrations of general anaesthetics on reconstructed peptidergic synapses and electrical synapses in the intact brain of the mollusc Lymnaea stagnalis (L.) are described. 2. At identified, reconstructed, FMRFamidergic synapses, chemical synaptic transmission is completely blocked in 2% halothane. 3. Inhibitory postsynaptic responses to directly applied FMRFamide are maintained in 2% halothane and are enhanced in 1% halothane, unlike excitatory responses which are abolished at this concentration. 4. Met-enkephalin normally produces inhibitory responses on postsynaptic PeA neurones, but these are non-reversibly abolished by halothane, whose presence induces novel, dose-dependent, enkephalinergic depolarising responses. 5. The biophysical effects of volatile anaesthetics and sodium pentobarbital on neuronal membranes have been described and they are shown to have opposite dose-dependent effects on input resistance, input conductance and time constant of the electrically coupled neurones VD1 and RPD2. 6. Volatile anaesthetics decouple the neurones VD1 and RPD2 in a dose dependent manner, whilst sodium pentobarbital either enhances coupling or has no effect, depending on the concentration used.