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

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

Results: 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.

Conclusions: 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.