Oral thermosensing by murine trigeminal neurons: modulation by capsaicin, menthol and mustard oil

Abstract

Key points Orosensory thermal trigeminal afferent neurons respond to cool, warm, and nociceptive hot temperatures with the majority activated in the cool range. Many of these thermosensitive trigeminal orosensory afferent neurons also respond to capsaicin, menthol, and/or mustard oil (allyl isothiocyanate) at concentrations found in foods and spices. There is significant but incomplete overlap between afferent trigeminal neurons that respond to oral thermal stimulation and to the above chemesthetic compounds. Capsaicin sensitizes warm trigeminal thermoreceptors and orosensory nociceptors; menthol attenuates cool thermoresponses. Abstract When consumed with foods, mint, mustard, and chili peppers generate pronounced oral thermosensations. Here we recorded responses in mouse trigeminal ganglion neurons to investigate interactions between thermal sensing and the active ingredients of these plants – menthol, allyl isothiocyanate (AITC), and capsaicin, respectively – at concentrations found in foods and commercial hygiene products. We carried out in vivo confocal calcium imaging of trigeminal ganglia in which neurons express GCaMP3 or GCAMP6s and recorded their responses to oral stimulation with thermal and the above chemesthetic stimuli. In the V3 (oral sensory) region of the ganglion, thermoreceptive neurons accounted for ∼10% of imaged neurons. We categorized them into three distinct classes: cool‐responsive and warm‐responsive thermosensors, and nociceptors (responsive only to temperatures ≥43–45 °C). Menthol, AITC, and capsaicin also elicited robust calcium responses that differed markedly in their latencies and durations. Most of the neurons that responded to these chemesthetic stimuli were also thermosensitive. Capsaicin and AITC increased the numbers of warm‐responding neurons and shifted the nociceptor threshold to lower temperatures. Menthol attenuated the responses in all classes of thermoreceptors. Our data show that while individual neurons may respond to a narrow temperature range (or even bimodally), taken collectively, the population is able to report on graded changes of temperature. Our findings also substantiate an explanation for the thermal sensations experienced when one consumes pungent spices or mint.

Transduction mechanisms for cold temperature in mouse trigeminal and vagal ganglion neurons innervating different peripheral organs

“…Few previous studies have performed a functional characterization of cold responses in mice lacking both TRPM8 and TRPA1. Previous studies in DRG and TG neurons have shown, using pharmacological tools, that there is a proportion of neurons that mediate cold responses via an unknown, TRPA1-/TRPM8-independent mechanism (Babes, Zorzon, & Reid, 2004;Leijon et al, 2019;Memon et al, 2017;Munns, AlQatari, & Koltzenburg, 2007). The molecular identity of this additional cold sensor remains to be characterized.…”

“…Our data therefore clearly showed that TRPM8 mediates the majority of cold responses in TG and all responses to mild temperature drops, whereas TRPA1 plays some role in mediating additional high threshold cold responses. The involvement of TRPM8 as a cold transducer in TG neurons has long been established, especially for low-threshold (>20 °C) thermoreceptors (Bautista et al, 2007;Leijon et al, 2019;Madrid et al, 2009;McKemy et al, 2002;Thut, Wrigley, & Gold, 2003). Evidence for the contribution of TRPA1 channels in cold sensing has been inconsistent and even sensitive to subtle changes in the testing paradigm employed (Winter, Gruschwitz, Eger, Touska, & Zimmermann, 2017).…”

Imaging sensory transmission and neuronal plasticity in primary sensory neurons with genetically-encoded voltage indicator, ASAP4.4-Kv

“…The intrinsic slow kinetics of GECIs permits mapping large numbers of neuronal assemblies in their native environments with conventional confocal microscopic approaches. Intensive studies using GECIs have characterized sensory coding of heat or cold 22,23,[29][30][31] , mechanical 29,31,32 , or chemical stimuli 33 in health and disease conditions. Due to the intrinsic fast kinetics of GEVIs, simultaneous imaging of dozens, hundreds, or thousands of DRG neurons at high spatial (millimeters) and temporal (milliseconds) resolution is an extremely challenging task and limited by current technological advances.…”

In vivo calcium imaging identifies functionally and molecularly distinct subsets of tongue-innervating mechanosensory neurons

“…Several studies have investigated mechanisms of temperature and chemosensation in the oral cavity, but few have addressed the cellular and molecular mechanisms of mechanosensation in lingual neurons (Dickman et al, 1987;Donnelly et al, 2018;Leijon et al, 2019;Poulos & Lende, 1970a, 1970bRobinson, 1992;Smith & Robinson, 1995;Yarmolinsky et al, 2016). This is particularly important as the tip of the tongue is exquisitely mechanosensitive with acuity comparable to that of the fingertip (Miles et al, 2018;Van Boven & Johnson, 1994).…”