GABAA Receptor Blockade Antagonizes the Immobilizing Action of Propofol but Not Ketamine or Isoflurane in a Dose-Related Manner

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Abstract
GABAA antagonist picrotoxin and the competitive GABAA 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 (ED50) 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 ED50 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 ED50 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 ED50 observed. Because strychnine only increased the immobilizing ED50 of propofol by approximately 50%, GABAA receptor antagonism accounted for the results seen with picrotoxin and gabazine. We conclude that GABAA antagonism can influence the ED50 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 GABAA receptor because antagonism of GABAA receptors for animals anesthetized with isoflurane produces results quantitatively and qualitatively similar to ketamine and markedly different from propofol....