Toxicology letters
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1. General anesthesia is achieved by anesthetic action in the central nervous system (CNS). 2. ⋯ The extent to which anesthetic action in the brain influences the spinal cord probably varies among anesthetics. Furthermore, anesthetics can indirectly influence the brain by their actions within the spinal cord, i.e. by modulating ascending transmission of sensory information.
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(1) The discovery of the non-anaesthetics has provided a unique opportunity for using novel modelling techniques to study the molecular mechanisms of anaesthesia. (2) We have selected the molecular similarity approach to investigate the importance of three-dimensional molecular fields, such as geometric shape and electrostatic potential, in (a) determining whether an agent exhibits anaesthetic activity and (b) in determining the in vivo potencies of active agents. (3) The results to date are both provocative and highly promising.
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(1) Considerable evidence has accumulated that the molecular target of general anesthetics in the central nervous system is the GABA(A) receptor, the major mediator of inhibitory synaptic transmission. This receptor is actually a family of ligand-gated chloride channel proteins, each a heteropentameric membrane-spanning structure. (2) Regional variation in anesthetic actions on the central nervous system may parallel a corresponding regional variation in pharmacological subtypes of GABA(A) receptors. These result from differential regional expression of approximately 18 subunit genes. (3) Receptors of varying subunit composition show differential sensitivity to GABA, modulatory drugs, and biological regulatory mechanisms. Regional variation in allosteric modulation of GABA(A) receptor binding and function can be reconstituted in certain recombinant receptor subunit combinations expressed in heterologous cells. (5) Differential sensitivity to anesthetics for various GABA(A) receptor subunits also allows the use of the chimeric and site-directed mutagenesis approach in attempting to define domains of the protein which participate in the binding and actions of anesthetics.
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A large body of evidence has accumulated in recent years pointing towards the GABA(A) receptor as a primary determinant of volatile anesthetic action (Franks and Lieb, 1994). Nevertheless, our understanding of the function of the central nervous system (CNS) remains sufficiently incomplete that other mechanisms of CNS depression remain to be examined. We have studied a new family of potassium (K+) channels which function as regulators of the baseline excitability of neuronal tissue. As such they must be considered potential targets for volatile anesthetic action and as a possible mechanism by which volatile anesthetics act to allow patients to undergo noxious surgical stimulation.
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1. The intravenous anaesthetic etomidate augments GABA-gated chloride currents (indirect action) and, at higher concentrations, evokes chloride currents in the absence of GABA (direct action). 2. ⋯ In contrast, the indirect effect of etomidate was retained, though its potency was reduced. 5. These findings indicate that there are distinct requirements for these dual actions of etomidate at GABA(A) receptors.