GABA(A) receptor blockade antagonizes the immobilizing action of propofol but not ketamine or isoflurane in a dose-related manner.
The enhancing action of propofol on gamma-amino-n-butyric acid subtype A (GABA(A)) receptors purportedly underlies its anesthetic effects. However, a recent study found that a GABA(A) antagonist did not alter the capacity of propofol to depress the righting reflex. We examined whether the noncompetitive GABA(A) antagonist picrotoxin and the competitive GABA(A) antagonist gabazine affected a different anesthetic response, immobility in response to a noxious stimulus (a tail clamp in rats), produced by propofol. This effect was compared with that seen with ketamine and isoflurane. Picrotoxin increased the 50% effective dose (ED(50)) for propofol by approximately 379%; gabazine increased it by 362%, and both antagonists acted in a dose-related manner with no apparent ceiling effect (i.e., no limit). Picrotoxin maximally increased the ED(50) for ketamine by approximately 40%-50%, whereas gabazine increased it by 50%-60%. The isoflurane minimum alveolar anesthetic concentration increased by approximately 60% with the picrotoxin and 70% with the gabazine infusion. The ED(50) for propofol was also antagonized by strychnine, a non-GABAergic glycine receptor antagonist and convulsant, to determine whether excitation of the central nervous system by a non-GABAergic mechanism could account for the increases in propofol ED(50) observed. Because strychnine only increased the immobilizing ED(50) of propofol by approximately 50%, GABA(A) receptor antagonism accounted for the results seen with picrotoxin and gabazine. We conclude that GABA(A) antagonism can influence the ED(50) for immobility of propofol and the non-GABAergic anesthetic ketamine, although to a different degree, reflecting physiologic antagonism for ketamine (i.e., an indirect effect via a modulatory effect on the neural circuitry underlying immobility) versus physiologic and pharmacologic antagonism for propofol (i.e., a direct effect by antagonism of propofol's mechanism of action). This study also suggests that the immobilizing action of isoflurane probably does not involve the GABA(A) receptor because antagonism of GABA(A) receptors for animals anesthetized with isoflurane produces results quantitatively and qualitatively similar to ketamine and markedly different from propofol.


CONCLUSIONS
IV picrotoxin and gabazine antagonized the immobilizing action of propofol in a dose-related manner, whereas antagonism of the immobilizing action of ketamine and isoflurane was similar, smaller than for propofol, and not dose-related. These results are consistent with a role for gamma-amino-n-butyric acid subtype A receptors in mediating propofol anesthesia but not ketamine or isoflurane anesthesia.
Bovill
James G
JG
Department of Anesthesia and Perioperative Care, University of California, San Francisco.
Sonner
James M
JM
Zhang
Yi
Y
Stabernack
Caroline
C
Abaigar
Wella
W
Xing
Yilei
Y
Laster
Michael J
MJ
D000778:Anesthetics, Dissociative / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D018684:Glycine Agents / Q000494:pharmacology; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D007530:Isoflurane / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007649:Ketamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D010852:Picrotoxin / Q000494:pharmacology; D015742:Propofol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013331:Strychnine / Q000494:pharmacology
D000778:Anesthetics, Dissociative; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D001640:Bicuculline; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D018684:Glycine Agents; D007530:Isoflurane; D007649:Ketamine; D010852:Picrotoxin; D015742:Propofol; D011724:Pyridazines; D013331:Strychnine; C049853:gabazine