Inflammation Increases Neuronal Sensitivity to General Anesthetics
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Bibliographic record
Abstract
AbstractAbstract The inflammatory cytokine interleukin-1β increased γ-aminobutyric acidergic inhibitory currents in the presence of etomidate or isoflurane in cultured mouse hippocampal and cortical neurons. In a mouse model of sepsis, behavioral sensitivity to both anesthetics was increased. The clinical relevance of these findings will require studies of specific anesthetic endpoints in patients with systemic inflammation. 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 (GABA A ) receptors expressed on the surface of neurons, which supports the hypothesis that inflammation increases up-regulation of GABA A 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 GABA A receptor activity in vitro correlates with enhanced sensitivity for GABA A receptor–dependent behavioral endpoints in vivo .
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it