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

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 µM) 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 µM) 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.