Investigations into pharmacological antagonism of general anaesthesia

Abstract

1 The eects of convulsant drugs, and of thyrotropin releasing hormone (TRH), were examined on the general anaesthetic actions of ketamine, ethanol, pentobarbitone and propofol in mice. The aim was to investigate the possibility of selective antagonism, which, if seen, would provide information about the mechanism of the anaesthesia. 2 The general anaesthetic eects of ketamine were unaected by bicuculline; antagonism was seen with 4-aminopyridine and signi®cant potentiation with 300 mg kg 71 NMDLA (N-methyl-DLaspartate). The calcium agonist, Bay K 8644, potentiated the anaesthesia produced by ketamine and antagonism of such anaesthesia was seen with TRH. 3 A small, but signi®cant, antagonism of the general anaesthesia produced by ethanol was seen with bicuculline, and a small, signi®cant, potentiation with 4-aminopyridine. There was an antagonist eect of TRH, but no eect of NMDLA. 4 Potentiation of the anaesthetic eects of pentobarbitone was seen with NMDLA and with 4-aminopyridine and the lower dose of bicuculline (2.7 mg kg 71) also caused potentiation. There was no signi®cant change in the ED 50 value for pentobarbitone anaesthesia with TRH. 5 Bicuculline did not alter the anaesthetic actions of propofol, while potentiation was seen with NMDLA and 4-aminopyridine. TRH had no signi®cant eect on propofol anaesthetic, but Bay K 8644 at 1 mg kg 71 signi®cantly potentiated the anaesthesia. 6 These results suggest that potentiation of GABA A transmission or inhibition of NMDA receptor-mediated transmission do not appear to play a major role in the production of general anaesthesia by the agents used.

Propofol block of Ih contributes to the suppression of neuronal excitability and rhythmic burst firing in thalamocortical neurons

“…This is an ED 50 dose for loss‐of‐righting reflex (Lingamaneni et al ., 2001), which is an animal model for unconsciousness. Behavioral observations and measurements of righting reflex were carried out as previously described (Little et al ., 2000; Lingamaneni et al ., 2001). Body temperature was maintained at 38 °C using a heating pad placed beneath the mice.…”

“…Propofol achieves these actions in part via allosteric regulation of GABA A receptors (Hales & Lambert, 1991; Krasowski et al ., 2001), and recent studies on knock‐in mutant mice suggest that these effects of propofol at the molecular level are of considerable behavioral significance (Jurd et al ., 2003). However, a variety of behavioral studies have shown that the anticonvulsant and sedative actions of propofol are incompletely blocked by GABA A receptor antagonists (Little et al ., 2000; Ohmori et al ., 2004), indicating that additional unidentified mechanisms are involved.…”

Anaesthetic modulation of synaptic transmission in the mammalian CNS

“…24 Finally, administration of the GABA A agonist muscimol to an intact animal does not result in general anaesthesia, nor can anaesthesia be reversed simply by administering a GABA A antagonist, such as bicuculline. 55 These caveats should not be taken as evidence that anaesthetic interactions with the GABA A receptor are unimportant in causing anaesthesia. For many anaesthetics, the potentiating effect of anaesthetics on the GABA receptors is a major component of their mode of action.…”

Effect of thiopental sodium on N-methyl-D-aspartate-gated currents

“…4 We know that GABA A receptors are not the only target for general anesthetics. 5 The NMDA receptor may also mediate the action of barbiturates. It has been reported that barbiturates decrease NMDAgated currents in the spinal cord but have no effect on amino acid pathway gated currents.…”