Does glycine antagonism underlie the excitatory effects of methohexitone and propofol?
We have investigated the pharmacological basis of CNS excitation that occurs in association with general anaesthesia in mice. Propofol produced sustained clonic movements during anaesthesia. Methohexitone produced intermittent non-rhythmic jerking during anaesthesia. Ethanol and pentobarbitone produced anaesthesia without associated clonic movements. Doses of all anaesthetic drugs were equipotent. Surface EEG recordings showed paroxysmal discharges consistent with interictal manifestations of cortical seizures with methohexitone or propofol, but not with ethanol or pentobarbitone. Strychnine, a glycine antagonist without effects on the cerebral cortex, and bicuculline, a GABAA antagonist with effects on the cerebral cortex, were used in doses that were equipotent-0.5 log units less than the ED10 for clonic convulsions. Strychnine potentiated both excitatory behaviour and EEG paroxysmal discharges when given with methohexitone or propofol, but not with ethanol or pentobarbitone. Bicuculline did not affect either behaviour or EEG with any of the anaesthetic drugs. Our data show that methohexitone and propofol produced CNS excitation, while pentobarbitone and ethanol did not. We propose that the pharmacological basis of this excitation may be glycine antagonism occurring in subcortical structures.
Dolin
S J
SJ
Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge.
Smith
M B
MB
Soar
J
J
Morris
P J
PJ
D000768:Anesthesia, General / Q000009:adverse effects*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects*; D004569:Electroencephalography / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology; D005998:Glycine / Q000037:antagonists & inhibitors*; D008297:Male; D008723:Methohexital / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D010424:Pentobarbital / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced*; D013331:Strychnine / Q000494:pharmacology
D000431:Ethanol; D008723:Methohexital; D013331:Strychnine; D010424:Pentobarbital; D005998:Glycine; D001640:Bicuculline; D015742:Propofol