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

Br J Pharmacol. 2010 Feb;159(4):872-8. doi: 10.1111/j.1476-5381.2009.00583.x. Epub 2010 Jan 25.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Inhalation
  • Anesthetics, Inhalation / administration & dosage*
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Immobilization
  • Infusions, Parenteral
  • Isoflurane / administration & dosage*
  • Male
  • Motor Activity / drug effects*
  • Pain Threshold / drug effects*
  • Rats
  • Rats, Long-Evans
  • Sodium Channel Blockers / administration & dosage*
  • Sodium Channels / drug effects*
  • Sodium Channels / metabolism
  • Tetrodotoxin / administration & dosage*
  • Veratridine / administration & dosage*


  • Anesthetics, Inhalation
  • Sodium Channel Blockers
  • Sodium Channels
  • Tetrodotoxin
  • Veratridine
  • Isoflurane