Anesthetic Pharmacology of the Mint Extracts L-Carvone and Methyl Salicylate
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2022-01-01
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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 (GABA<sub>A</sub>) receptors, N-methyl-D-aspartate (NMDA) receptors, and type-2 voltage-gated sodium (Na<sub>v</sub>1.2) 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 GABA<sub>A</sub> 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% Na<sub>v</sub>1.2 channel inhibition by both compounds and 30% potentiation of GABA<sub>A</sub> 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.
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Pharmacology.