New insights in the systemic and molecular underpinnings of general anesthetic actions mediated by γ-aminobutyric acid A receptors

Abstract

Purpose of review: The review highlights novel insights into the role of γ-aminobutyric acid A (GABAA) receptors in mediating clinically relevant actions of anesthetic agents.

Recent findings: GABAA receptors in the hippocampus are located on glutamatergic pyramidal cells and GABAergic interneurons. Etomidate-induced inhibition of a synaptic correlate of learning and memory is caused by receptors on nonpyramidal neurons, likely on interneurons that incorporate α5 subunits. Selective enhancement of α2 subunit containing GABAA receptors in the spinal cord provides antihyperalgesia against inflammatory and neuropathic pain without causing sedation, motor impairment, and tolerance development. Inflammation, traumatic brain injury, and exposure to anesthetic agents modify the expression patterns of GABAA receptors in a subtype-specific manner. These modifications may persist for weeks. The neuroactive steroid alphaxalone causes fast-onset and short-duration anesthesia in humans. Cardiovascular and respiratory side-effects are less severe than with propofol.

Summary: Identification of the molecular and cellular substrates involved in anesthesia and insights into disease and drug-induced alterations in the expression patterns of GABAA receptors in the central nervous system are emphasizing the need for individualized anesthesia care. Introducing neuroactive steroids into clinical anesthesia is expected to reduce cardiovascular and respiratory side-effects.

Figure 1. GABA_A receptors and anesthetic actions

GABA_A receptors assemble from five protein subunits.[47] Most GABA_A receptors are composed of two α-, two β- and a γ-subunit. However, nineteen different protein subunits are expressed in central neurons, giving rise to many potentially existing receptor subtypes. Some of these are indicated on the upper right. There is evidence that receptor subtypes harboring α1- and β2 subunits mediate the sedative actions of benzodiazepines, etomidate and propofol.[48,49] Furthermore, GABA_A receptors incorporating α2-subunits mediate the anxiolytic and antihyperalgesic actions of benzodiazepines.[18,50] α5-containing GABA_A receptors are densely expressed in the hippocampus and mediate the amnestic effect of anesthetics.[9] The amnestic, sedative, anxiolytic and hypnotic properties of anesthetic agents are mediated by GABA_A receptors in the brain whereas antihyperalgesia and immobility is caused by spinal receptors.[2]

Figure 2

Factors affecting the expression pattern of GABA_A receptor subunits, potentially altering the patient’s sensitivity to anesthetic drugs.