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ANESTHETIC PHARMACOLOGY

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

Department of Anesthesia and Perioperative Care, University of California, San Francisco

Address correspondence and reprint requests to James M. Sonner, MD, Department of Anesthesiology and Perioperative Care, Room S-455I, Box 0464, 513 Parnassus Ave., University of California, San Francisco, CA 94143-0464. Address e-mail to sonnerj{at}anesthesia.ucsf.edu

The enhancing action of propofol on -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 (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%, GABA_A receptor antagonism accounted for the results seen with picrotoxin and gabazine. We conclude that GABA_A 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 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.

IMPLICATIONS: 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 -amino-n-butyric acid subtype A receptors in mediating propofol anesthesia but not ketamine or isoflurane anesthesia.

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