title: Inflammation Increases Neuronal Sensitivity to General Anesthetics.
abstract: BACKGROUND
  Critically 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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  IL-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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: 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.
authors.forename: Sinziana
authors.initials: S
authors.lastname: Avramescu
authors.forename: Dian-Shi
authors.initials: DS
authors.lastname: Wang
authors.forename: Irene
authors.initials: I
authors.lastname: Lecker
authors.forename: William T H
authors.initials: WT
authors.lastname: To
authors.forename: Antonello
authors.initials: A
authors.lastname: Penna
authors.forename: Paul D
authors.initials: PD
authors.lastname: Whissell
authors.forename: Lia
authors.initials: L
authors.lastname: Mesbah-Oskui
authors.forename: Richard L
authors.initials: RL
authors.lastname: Horner
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
mesh_terms: D018681:Anesthetics, General / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects; D005045:Etomidate / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology*; D007530:Isoflurane / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000187:drug effects
chemical_list: D018681:Anesthetics, General; D018685:Anesthetics, Inhalation; D006993:Hypnotics and Sedatives; D008070:Lipopolysaccharides; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D007530:Isoflurane; D005045:Etomidate