|Title||Bidirectional modulation of isoflurane potency by intrathecal tetrodotoxin and veratridine in rats.|
|Publication Type||Journal Article|
|Year of Publication||2010|
|Authors||Zhang Y, Guzinski M, Eger EI, Laster MJ, Sharma M, Harris RA, Hemmings HC|
|Journal||Br J Pharmacol|
|Date Published||2010 Feb|
|Keywords||Administration, 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|
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.
|Alternate Journal||Br J Pharmacol|
|PubMed Central ID||PMC2829212|
|Grant List||R01 AA006399 / AA / NIAAA NIH HHS / United States |
R01 GM058055 / GM / NIGMS NIH HHS / United States
GM58055 / GM / NIGMS NIH HHS / United States
P01 GM047818 / GM / NIGMS NIH HHS / United States
1P01GM47818 / GM / NIGMS NIH HHS / United States