Molecular mechanisms of general anesthesia

Abstract

General anesthetics produce a widespread neurodepression in the central nervous system by enhancing inhibitory neurotransmission and reducing excitatory neurotransmission. However, the action mechanisms of general anesthetics are not completely understood. Moreover, the general anesthetic state comprises multiple components (amnesia, unconsciousness, analgesia, and immobility), each of which is mediated by different receptors and neuronal pathways. Recently, neurotransmitter- and voltage-gated ion channels have emerged as the most likely molecular targets for general anesthetics. The gamma-aminobutyric acid type A (GABA(A)) receptors are leading candidates as a primary target of general anesthetics. This review summarizes current knowledge on how anesthetics modify GABA(A) receptor function.

Keywords: GABAA receptors; General anesthetics; Neurotransmitter-gated ion channels.

Fig. 1

Synaptic and extrasynaptic activation of γ-aminobutyric acid subtype A (GABA_A) receptors. Action potential dependent release of GABA into the synaptic cleft transiently activates GABA_A receptors in the postsynaptic membrane. This generates inhibitory postsynaptic currents (IPSCs). Extrasynaptic GABA_A receptors are activated by low concentrations of GABA in the extracellular space. These receptors have low desensitization rates and can produce a tonic current (continuous current). The tonic current is revealed by application of a GABA_A antagonist, Bicuculline, which inhibits the current. Many general anesthetics enhance the tonic current at clinically relevant concentrations. I_Tonic represents the amplitude of the steady state current.

Fig. 2

Potentiation of γ-aminobutyric acid subtype A (GABA_A) receptor-mediated inhibitory synaptic and tonic current by the general anesthetics. (A) The prolongation of miniature inhibitory synaptic currents (mIPSCs) by the slowing of current decay is shown. (B) Propofol prolongs the time-course of mIPSCs and slightly increases the peak amplitude of mIPSCs. (C) The schematic drawings used to calculate charge transfer (shaded area). Anesthetics produce a greater increased in charge transfer associated with the tonic current compared with mIPSCs.