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

Abstract

Purpose of the review This review highlights novel insights into the role of 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 non-pyramidal 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.

SAGE-217, A Novel GABAA Receptor Positive Allosteric Modulator: Clinical Pharmacology and Tolerability in Randomized Phase I Dose-Finding Studies

“…SAGE-217 was not associated with any SAEs across both studies. The pharmacological effects observed were anticipated and consistent with the GABA A receptor PAM mechanism of action and the pharmacologic profile of SAGE-217, with sedation observed at peak drug exposure [30]. Overall, the tolerability profile of SAGE-217 supported advancement of SAGE-217 into further development in mood disorders.…”

Role of estradiol in mediation of etomidate‐caused seizure‐like activity in neonatal rats

“…These data are consistent with the possibility that etomidate causes neurotoxic effects in the developing brain, at least in part, by potentiating GABA A R‐mediated depolarizing Cl − currents (Mesbah‐Oskui and Horner, 2016; Antkowiak and Rudolph, 2016). In addition, gonadal steroids have rapid effects through classic and non‐classic receptors at the membrane or in the cytosol to change second messenger pathways and ion channel function which in turn regulates neuronal excitability activity (Handa and Weiser, 2014).…”

Role of GABAA receptor subtypes in the behavioural effects of intravenous general anaesthetics

“…This chemical diversity appeared to preclude involvement of a common molecular anaesthetic target, such as a classical drug-receptor interaction, as no obvious structure-activity relationship was evident. [1][2][3][4][5] Such diversity led early theories of general anaesthetic activity to focus on non-specific interactions within the central nervous system (CNS). More than a century ago, Meyer and Overton reported a striking correlation between the oil:water partition coefficients of a range of anaesthetic compounds and their ability to immobilize tadpoles, i.e.…”