Anesthetic pharmacology of the mint extracts L-carvone and methyl salicylate

Introduction: Hydrocarbons with sufficient water solubility allosterically
modulate anesthetic-sensitive ion channels. Mint extracts L-carvone and
methyl salicylate water solubility exceeds modulation cutoff values for
γ-amino butyric acid type A (GABAA) receptors, N-methyl-D-aspartate (NMDA)
receptors, and type-2 voltage-gated sodium (Nav1.2) channels. We
hypothesized that mint extracts modulate these channels at concentrations
that anesthetize rats. Methods:Channels were expressed separately in frog
oocytes and studied using 2-electrode voltage clamp techniques at drug
concentrations up to 10 mM. Normalized current effects were fit to Hill
equations. Mint compounds were formulated in a lipid emulsion and
administered IV to rats. When unresponsive to the tail clamp, rats were
exsanguinated, and plasma drug concentrations were measured. Results: Both
mint compounds caused concentration-dependent inhibition of all channels
except for methyl salicylate which inhibited GABAA receptors at low
concentrations and potentiated at high concentrations. Plasma drug
concentrations in anesthetized rats were 7.9 mM for L-carvone and 2.7 mM
for methyl salicylate. This corresponded to ≥53% NMDA receptor inhibition
and ≥78% Nav1.2 channel inhibition by both compounds and 30% potentiation
of GABAA receptors by methyl salicylate. Conclusion: L-Carvone and methyl
salicylate allosterically modulate cell receptor targets important to
molecular actions of conventional anesthetics at concentrations that also
induce general anesthesia in rats.