The Trpa1 Agonist Cinnamaldehyde Acts as a Local Anesthetic Inhibiting Voltage-Gated Sodium Channels in Sensory Neurons

Abstract

Cinnamaldehyde (CA) is a highly reactive compound that has been used in experimental models of neurogenic inflammation as specific agonist of the broadly tuned chemosensor TRPA1. In several models of chemonociception in mice and humans, we have found that CA only produces very weak avoidance, pain or visceral irritation responses. Furthermore, CA induces a dramatic decrease in the velocity of conduction and the amplitude of compound action potentials in the mouse tail. Noting the structural similarities between CA and classical local anesthetics, we investigated whether CA inhibits voltage-gated sodium channels (VGSC) expressed in sensory neurons. We found that CA inhibits TTX-sensitive voltage-dependent sodium currents in a concentration dependent manner in mouse trigeminal neurons with an IC50 of 1.5 mM. TTX-resistant sodium currents were inhibited with an IC50 of 0.8 mM. TTX-sensitive VGSC recorded in the immortalized DRG neuron-derived F11 cells were inhibited with an IC50 of 1.3 mM. CA modified the gating of TTX-sensitive sodium channels, inducing concentration-dependent shifts of the activation curve to depolarized voltages and shifts of the availability curve to more hyperpolarized voltages. In the presence of CA, the corresponding slope factors became significantly larger. CA-induced inhibition was enhanced at depolarized holding potentials. Inhibition of TTX-sensitive sodium channels was not frequency dependent and can occur when the channels are in resting/closed state(s). We conclude that CA inhibits VGSC in sensory neurons at concentrations that can be pharmacologically relevant, and that the mechanism of inhibition shares similarities with the action of local anesthetics.