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The effects 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. The general anaesthetic effects of ketamine were unaffected by bicuculline; antagonism was seen with 4-aminopyridine and significant potentiation with 300 mg kg−1 NMDLA (N-methyl-DL-aspartate). The calcium agonist, Bay K 8644, potentiated the anaesthesia produced by ketamine and antagonism of such anaesthesia was seen with TRH. A small, but significant, antagonism of the general anaesthesia produced by ethanol was seen with bicuculline, and a small, significant, potentiation with 4-aminopyridine. There was an antagonist effect of TRH, but no effect of NMDLA. Potentiation of the anaesthetic effects of pentobarbitone was seen with NMDLA and with 4-aminopyridine and the lower dose of bicuculline (2.7 mg kg−1) also caused potentiation. There was no significant change in the ED50 value for pentobarbitone anaesthesia with TRH. Bicuculline did not alter the anaesthetic actions of propofol, while potentiation was seen with NMDLA and 4-aminopyridine. TRH had no significant effect on propofol anaesthetic, but Bay K 8644 at 1 mg kg−1 significantly potentiated the anaesthesia. These results suggest that potentiation of GABAA 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. Keywords: General anaesthesia, convulsant, TRH, righting reflex Introduction The mechanism(s) by which drugs produce general anaesthesia are not well understood (Halsey, 1992; Angel, 1993; Little, 1996). Many different effects of general anaesthetic drugs on synapses have been demonstrated, but the most important aspect, often neglected, is the possible relationship between these synaptic actions and the production of general anaesthesia. One problem in the investigation of such a relationship has been the lack of specific antagonists for general anaesthesia. There have been a small number of studies reporting antagonism of general anaesthesia with various drugs but no systematic investigation has been made and usually only one or two anaesthetics have been studied. Compounds which have been reported to antagonize anaesthesia are 4-aminopyridine (4-AP), against ethanol and ketamine (Agostin et al., 1980; Sellin & Laakso, 1987), and thyrotropin releasing hormone (TRH) against ethanol and pentobarbitone (Breese et al., 1974; French et al., 1993; Matsushita et al., 1995). Anticholinesterase agents have also been shown to have some effects (Livingston & Waterman, 1978; Leeuwin et al., 1984). Antagonism of the general anaesthetic effects of ethanol, pentobarbitone and argon was reported with the calcium channel agonist, Bay K 8644 (Dolin et al., 1988). The only reproducible and consistent way so far demonstrated in which general anaesthesia can be antagonized is by the application of high pressure (Lever et al., 1971). Increasing the ambient pressure to approximately 80–100 atmospheres reverses the anaesthetic effects of a variety of types of compound, including inhalational anaesthetics, barbiturates and steroids (Halsey & Wardley-Smith, 1975; Halsey et al., 1978; Miller & Wilson, 1978). In these studies, after the application of pressure following administration of anaesthetic, the animals recovered their righting reflex and appeared to be able to move normally. Pressure alone produces hyperexcitability and convulsions, and this can be demonstrated using helium gas, which has little general anaesthetic action itself, or by hydrostatic pressure (Lever et al., 1971). Evidence has been presented that the effects of pressure which prevent general anaesthesia are exerted at different neuronal sites than those at which the hyperexcitability is produced (Miller, 1977) but pressure reversal of general anaesthesia was demonstrated in recordings of evoked somatosensory responses in rats (Angel et al., 1980). The mechanism of the changes produced by pressure are not fully understood. High pressure does not appear to decrease the effects of GABA at GABAA receptors (Little, 1982) but the effects of NMDA on hippocampal CA1 cells was found to be increased (Zinebi et al., 1988). Daniels et al. (1991) found that depression by pentobarbitone of kainate responses in receptors expressed in oocytes was not affected by pressure. The main synaptic actions which have been suggested to cause general anaesthesia are increases in the effects of GABA (at GABAA receptors), decreases in excitatory amino acid transmission (Sawada & Yamamoto, 1985; Anis et al., 1983) and alterations in various ion channels, such as calcium (Kress et al., 1987; Llinas, 1988; Twombly et al., 1990) and potassium (Nicoll & Madison, 1982). Potentiation of the effects of GABA is seen with many different types of compound, such as barbiturates (Nicoll et al., 1975), steroids (Harrison & Simmonds, 1984), inhalational agents (Longon et al., 1993) and propofol (Collins, 1988). However such potentiation is also seen with benzodiazepines, which do not produce the state which we know as general anaesthesia until near lethal doses (Little & Bichard, 1984), although these drugs potentiate the general anaesthetic actions of other drugs. The present study is a systematic investigation of the effects of convulsants and thyrotropin releasing hormone (TRH) on general anaesthesia, to determine the extent of any antagonism and to see what information could be obtained about the mechanism by which the anaesthesia was produced. The anaesthetics were ketamine, ethanol, pentobarbitone and propofol, chosen because they represent different chemical classes of compound and because their synaptic actions have been widely studied. The convulsants were chosen on the basis of the extent of knowledge of their mechanism of action and previous reports of antagonism of general anaesthesia. Bicuculline is a specific GABAA receptor antagonist; NMDLA (N-methyl-DL-aspartate) is an excitatory amino acid agonist with selective actions at the NMDA subtype of receptor; 4-aminopyridine (4-AP) is a potassium channel blocker, previously reported to have antagonist actions against general anaesthesia (Agostin et al., 1980; Sellin & Laakso, 1987), which causes a non-selective blockade of voltage-dependent potassium channels (Griffith & Sim, 1990), with increased intracellular calcium concentrations (Heemskerk et al., 1991), and increased release of many transmitters. Bay K 8644 is a dihydropyridine which increases the conductance of the ‘L'-subtype of voltage-sensitive calcium channels (Freedman & Miller, 1984). The effects of TRH were also examined in view of the previous reports of antagonism of anaesthesia by TRH (Breese et al., 1974; French et al., 1993; Matsushita et al., 1995). |
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