• Sinziana Avramescu, Dian-Shi Wang, Irene Lecker, William T H To, Antonello Penna, Paul D Whissell, Lia Mesbah-Oskui, Richard L Horner, and Beverley A Orser.
• From the Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (S.A., B.A.O.); and Departments of Anesthesia (S.A., B.A.O.), Physiology (D.-S.W., I.L., W.T.H.T., A.P., R.L.H., B.A.O.), Psychology (P.D.W.), and Medicine (L.M.-O., R.L.H.), University of Toronto, Toronto, Ontario, Canada.
• Anesthesiology. 2016 Feb 1; 124 (2): 417-27.

BackgroundCritically ill patients with severe inflammation often exhibit heightened sensitivity to general anesthetics; however, the underlying mechanisms remain poorly understood. Inflammation increases the number of γ-aminobutyric acid type A (GABAA) receptors expressed on the surface of neurons, which supports the hypothesis that inflammation increases up-regulation of GABAA receptor activity by anesthetics, thereby enhancing the behavioral sensitivity to these drugs.MethodsTo mimic inflammation in vitro, cultured hippocampal and cortical neurons were pretreated with interleukin (IL)-1β. Whole cell patch clamp methods were used to record currents evoked by γ-aminobutyric acid (GABA) (0.5 μM) in the absence and presence of etomidate or isoflurane. To mimic inflammation in vivo, mice were treated with lipopolysaccharide, and several anesthetic-related behavioral endpoints were examined.ResultsIL-1β increased the amplitude of current evoked by GABA in combination with clinically relevant concentrations of either etomidate (3 μM) or isoflurane (250 μM) (n = 5 to 17, P < 0.05). Concentration-response plots for etomidate and isoflurane showed that IL-1β increased the maximal current 3.3-fold (n = 5 to 9) and 1.5-fold (n = 8 to 11), respectively (P < 0.05 for both), whereas the half-maximal effective concentrations were unchanged. Lipopolysaccharide enhanced the hypnotic properties of both etomidate and isoflurane. The immobilizing properties of etomidate, but not isoflurane, were also increased by lipopolysaccharide. Both lipopolysaccharide and etomidate impaired contextual fear memory.ConclusionsThese results provide proof-of-concept evidence that inflammation increases the sensitivity of neurons to general anesthetics. This increase in anesthetic up-regulation of GABAA receptor activity in vitro correlates with enhanced sensitivity for GABAA receptor-dependent behavioral endpoints in vivo.

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