Cholinergic modulation of sevoflurane potency in cortical and spinal networks in vitro.
BACKGROUND
Victims of organophosphate intoxication with cholinergic crisis may have need for sedation and anesthesia, but little is known about how anesthetics work in these patients. Recent studies suggest that cholinergic stimulation impairs gamma-aminobutyric acid type A (GABAA) receptor function. Because GABAA receptors are major targets of general anesthetics, the authors investigated interactions between acetylcholine and sevoflurane in spinal and cortical networks.


METHODS
Cultured spinal and cortical tissue slices were obtained from embryonic and newborn mice. Drug effects were assessed by extracellular voltage recordings of spontaneous action potential activity.


RESULTS
Sevoflurane caused a concentration-dependent decrease in spontaneous action potential firing in spinal (EC50=0.17+/-0.02 mM) and cortical (EC50=0.29+/-0.01 mM) slices. Acetylcholine elevated neuronal excitation in both preparations and diminished the potency of sevoflurane in reducing action potential firing in cortical but not in spinal slices. This brain region-specific decrease in sevoflurane potency was mimicked by the specific GABAA receptor antagonist bicuculline, suggesting that (1) GABAA receptors are major molecular targets for sevoflurane in the cortex but not in the spinal cord and (2) acetylcholine impairs the efficacy of GABAA receptor-mediated inhibition. The latter hypothesis was supported by the finding that acetylcholine reduced the potency of etomidate in depressing cortical and spinal neurons.


CONCLUSIONS
The authors raise the question whether cholinergic overstimulation decreases the efficacy of GABAA receptor function in patients with organophosphate intoxication, thereby compromising anesthetic effects that are mediated predominantly via these receptors such as sedation and hypnosis.
Grasshoff
Christian
C
Department of Anesthesiology, University of Tuebingen, Tuebingen, Germany. christian.grasshoff@uni-tuebingen.de
Drexler
Berthold
B
Hentschke
Harald
H
Thiermann
Horst
H
Antkowiak
Bernd
B
D000109:Acetylcholine / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D018678:Cholinergic Agents / Q000494:pharmacology*; D004347:Drug Interactions; D005045:Etomidate / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008738:Methyl Ethers / Q000494:pharmacology*; D051379:Mice; D000077149:Sevoflurane; D013116:Spinal Cord / Q000187:drug effects*
D018685:Anesthetics, Inhalation; D018678:Cholinergic Agents; D008738:Methyl Ethers; D000077149:Sevoflurane; D000109:Acetylcholine; D005045:Etomidate