Self- and Cross-desensitization of Oral Irritation by Menthol and Cinnamaldehyde (CA) via Peripheral Interactions at Trigeminal Sensory Neurons

Abstract

Menthol and cinnamaldehyde (CA) are plant-derived spices commonly used in oral hygiene products, chewing gum, and many other applications. However, little is known regarding their sensory interactions in the oral cavity. We used a human psychophysics approach to investigate the temporal dynamics of oral irritation elicited by sequential application of menthol and/or CA, and ratiometric calcium imaging methods to investigate activation of rat trigeminal ganglion (TG) cells by these agents. Irritancy decreased significantly with sequential oral application of menthol and CA (self-desensitization). Menthol cross-desensitized irritation elicited by CA, and vice versa, over a time course of at least 60 min. Seventeen and 19% of TG cells were activated by menthol and CA, respectively, with ∼50% responding to both. TG cells exhibited significant self-desensitization to menthol applied at a 5, but not 10, min interval. They also exhibited significant self-desensitization to CA at 400 but not 200 μM. Menthol cross-desensitized TG cell responses to CA. CA at a concentration of 400 but not 200 μM also cross-desensitized menthol-evoked responses. The results support the argument that the perceived reductions in oral irritancy and cross-interactions between menthol and CA and menthol observed (at least at short interstimulus intervals) can be largely accounted for by the properties of trigeminal sensory neurons innervating the tongue.

Eugenol and carvacrol excite first- and second-order trigeminal neurons and enhance their heat-evoked responses

“…Eugenol activated 23% of TG cells and 7.6 percent of DRG cells, whereas carvacrol activated 30.4% of TG and 21.3% of DRG cells. The incidences of responsiveness to menthol (28.8% and 25.3% for TG and DRG cells, respectively), AITC (38.3% and 33.4%) and capsaicin (62.9% and 56.5%) were similar to previously published data (Klein et al, 2011a-c). Fig.…”

“…The ganglia were triturated and TG and DRG cells were processed as previously described (Klein et al, 2011a, Klein et al, 2011b) and plated onto glass coverslips pre-treated with poly-D-lysine. Cells were given fresh media after one hour and imaged within 48 hours.…”

High-Concentration L-Menthol Exhibits Counter-Irritancy to Neurogenic Inflammation, Thermal and Mechanical Hyperalgesia Caused by Trans-cinnamaldehyde

“…45 However, it has been proposed that analgesic effect of L-menthol may include several mechanisms, such as desensitization of TRPV1-fibers, stimulation of κ-opioid receptors and enhancement of central glutamate-facilitated gate-control mechanisms. 21,29,33,49,67 …”

The Development of a Menthol Solution for Use during Sport and Exercise

“…Habitual menthol use may alter the threshold at which TRPM8 channels and the trigeminal nerve are stimulated [37][38][39][40], ultimately habituating thermal sensation [37,38]. Despite no statistically significant differences in the present investigation, menthol concentrations of 0.095-0.105% may lead to small increases in trigeminal stimulation, concomitantly conferring benefits such as an increase in ventilation [3,16], reduced thermal sensation [18] and thirst [14], and improved thermal comfort [9] when exposed to the oral cavity.…”