Department of Anesthesiology

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Bidirectional modulation of isoflurane potency by intrathecal tetrodotoxin and veratridine in rats.

TitleBidirectional modulation of isoflurane potency by intrathecal tetrodotoxin and veratridine in rats.
Publication TypeJournal Article
Year of Publication2010
AuthorsZhang Y, Guzinski M, Eger EI, Laster MJ, Sharma M, Harris RA, Hemmings HC
JournalBr J Pharmacol
Volume159
Issue4
Pagination872-8
Date Published2010 Feb
ISSN1476-5381
KeywordsAdministration, Inhalation, Anesthetics, Inhalation, Animals, Dose-Response Relationship, Drug, Drug Interactions, Immobilization, Infusions, Parenteral, Isoflurane, Male, Motor Activity, Pain Threshold, Rats, Rats, Long-Evans, Sodium Channel Blockers, Sodium Channels, Tetrodotoxin, Veratridine
Abstract

BACKGROUND AND PURPOSE: Results from several studies point to voltage-gated Na(+) channels as potential mediators of the immobility produced by inhaled anaesthetics. We hypothesized that the intrathecal administration of tetrodotoxin, a drug that blocks Na(+) channels, should enhance anaesthetic potency, and that concurrent administration of veratridine, a drug that augments Na(+) channel opening, should reverse the increase in potency.

EXPERIMENTAL APPROACH: We measured the change in isoflurane potency for reducing movement in response to a painful stimulus as defined by MAC (minimum alveolar concentration of anaesthetic required to abolish movement in 50% of subjects) caused by intrathecal infusion of various concentrations of tetrodotoxin into the lumbothoracic subarachnoid space of rats, and the change in MAC caused by the administration of a fixed dose of tetrodotoxin plus various doses of intrathecal veratridine.

KEY RESULTS: Intrathecal infusion of tetrodotoxin (0.078-0.63 microM) produced a reversible dose-related decrease in MAC, of more than 50% at the highest concentration. Intrathecal co-administration of veratridine (1.6-6.4 microM) reversed this decrease in a dose-related manner, with nearly complete reversal at the highest veratridine dose tested.

CONCLUSIONS AND IMPLICATIONS: Intrathecal administration of tetrodotoxin increases isoflurane potency (decreases isoflurane MAC), and intrathecal administration of veratridine counteracts this effect in vivo. These findings are consistent with a role for voltage-gated Na(+) channel blockade in the immobility produced by inhaled anaesthetics.

DOI10.1111/j.1476-5381.2009.00583.x
Alternate JournalBr. J. Pharmacol.
PubMed ID20105175
PubMed Central IDPMC2829212
Grant List1P01GM47818 / GM / NIGMS NIH HHS / United States
GM58055 / GM / NIGMS NIH HHS / United States
P01 GM047818-150004 / GM / NIGMS NIH HHS / United States
R01 AA006399 / AA / NIAAA NIH HHS / United States
R01 AA006399-28 / AA / NIAAA NIH HHS / United States
R01 GM058055 / GM / NIGMS NIH HHS / United States