Grasshoff_2007_Toxicology_233_214

In scenarios of mass destruction it is likely that victims are intoxicated by organophosphates and, at the same time, physically injured. Organophosphate compounds produce excessive cholinergic overstimulation in the CNS via blocking acetylcholinesterase activity. The specifics of acute care and anaesthesia in physically traumatized and intoxicated patients are largely unknown. Recent studies in animals and human subjects demonstrated that acetylcholinesterase inhibitors reverse anaesthesia. Two distinct mechanisms are potentially involved. First, acetylcholine produces an excitatory drive onto neurons, thereby counterbalancing the inhibitory actions of anaesthetics. Anaesthesia is reversed because it critically depends on a distinctive depression of several central nervous functions. Second, cholinergic stimulation may affect the mechanisms by which anaesthetics mediate their depressant actions on central neurons. In this case acetylcholine reverses anaesthesia by decreasing the potency of anaesthetic agents. In order to identify potential mechanisms involved in cholinergic reversal of anaesthesia we have investigated interactions between acetylcholine and the volatile anaesthetic sevoflurane in isolated cortical brain slices. Our results provide evidence that cholinergic stimulation counterbalances the effects of general anaesthetics by increasing neuronal excitability, and, in addition, by decreasing anaesthetic potency. These findings imply that in patients suffering from organophosphorus intoxication dose requirements for general anaesthetics are considerably increased.