Avramescu S, Wang DS, Lecker I, To WTH, Penna A, Whissell PD, Mesbah-Oskui L, Horner RL and Orser BA. (2015) Anesthesiology (in press)
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 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 behavioral sensitivity to these drugs.
Methods: To mimic inflammation in vitro, cultured hippocampal and cortical neurons were pre-treated with interleukin-1β (IL-1β). Whole-cell patch clamp methods were used to record currents evoked by GABA (0.5 µM) in the absence and presence of etomidate or isoflurane. To mimic inflammation in vivo, mice were treated with lipopolysaccharide (LPS), and several anesthetic-related behavioral end points 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 = 5-17, P < 0.05). Concentration–response plots for etomidate and isoflurane showed that IL-1β increased the maximal current 3.3-fold (n = 5-9) and 1.5-fold (n = 8-11), respectively (P < 0.05 for both), whereas the half-maximal effective concentrations were unchanged. LPS enhanced the hypnotic properties of both etomidate and isoflurane. The immobilizing properties of etomidate, but not isoflurane, were also increased by LPS. Both LPS 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 end points in vivo.