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

Abstract

Key pointsr Orosensory thermal trigeminal afferent neurons respond to cool, warm, and nociceptive hot temperatures with the majority activated in the cool range.r 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.r There is significant but incomplete overlap between afferent trigeminal neurons that respond to oral thermal stimulation and to the above chemesthetic compounds.r 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 plantsmenthol, 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 ß10% 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 Sara Leijon received her PhD degree at Karolinska Institutet in Stockholm in 2016. During her doctoral studies she used in vitro whole-cell patch-clamp electrophysiology to study the audio-vestibular brainstem. Currently she works as a postdoctoral research associate at the University of Miami. Her career is focused on sensory neurophysiology. She is currently using in vivo functional imaging to study the two sensory ganglia, geniculate and trigeminal, that innervate the orofacial region. Amanda Neves has a MSc degree in Biomedical Engineering and, in 2018, she obtained her PhD at the University of Campinas, Brazil, investigating neuron-glia communication in dorsal root ganglia in relation to inflammatory pain.S. C. M. Leijon and others J Physiol 597.7 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.

Capsaicin pretreatment alleviates postoperative pain and reduces primary sensory neuron Ca2+ activity

“…Additionally, we monitored only the surface of DRG using confocal microscopy, and it is possible that the actual cell number activated by mild stimuli like large brush would be greater if we could image deeper into the DRG. Other groups and our own results also showed that the activated cell number is different depending on the stimulus in in vivo DRG and trigeminal ganglia Ca 2+ imaging (Kim et al, 2016;Chisholm et al, 2018;Leijon et al, 2019). More detailed analysis reveals that the increased cell number following plantar incision is mainly due to an increase in small to medium diameter cells.…”

Mouse trigeminal neurons respond to kokumi substances

“…This suggests that if koku sensations are indeed transmitted via somatosensory afferent of the trigeminal ganglion, there is not a uniform group of "koku-responding" neurons in that ganglion. Moreover, the relatively small population of trigeminal ganglion neurons dedicated to oral stimulation with kokumi substances (for instance compared with thermal-orosensitive neurons, Leijon et al 2019) suggest that it will remain a challenge to study koku-evoked somatosensations at the cellular level in the trigeminal ganglion. In particular, relating kokuresponsive neurons to molecular markers and eventually identifying a molecular receptor in trigeminal neurons will be challenging.…”

“…We used transgenic mice that express the calcium indicator GCaMP3 or GCaMP6s in sensory neurons, including those in the trigeminal ganglion (Leijon et al, 2019). GCaMP3 mice were obtained from X. Dong, Johns Hopkins and express GCaMP3 as a knock-in/knockout at the Pirt locus (Kim, Chu et al, 2014).…”

“…The trachea was exposed and cannulated for 6 facilitated respiration during oral stimulus presentation. A flexible tube was inserted through the esophagus to produce a uniform stimulus delivery into the oral cavity (Sollars and Hill 2005;Wu, Dvoryanchikov et al 2015;Leijon et al, 2019). Next, the mouse was placed in prone position for surgical exposure of the region of the trigeminal ganglion that innervates the oral cavity, V3 (Fig.…”

“…Kokumi peptide γ-Glu-Val-Gly 4.1.1 Trigeminal primary afferent neurons respond to the kokumi peptide γ-Glu-Val-GlyTo investigate if oral exposure to γ-Glu-Val-Gly (EVG) elicits trigeminal responses in vivo, the oral cavity of the mouse was superfused with 100 µM EVG. Because many trigeminal ganglion neurons are also sensitive to other sensory stimuli, for example temperature(Yarmolinsky et al, 2016;Leijon et al, 2019), EVG was preceded with a control stimulus consisting of artificial saliva at the same temperature and perfusion rate as the EVG application (Fig 3). Our results show that EVG (100 µM) applied orally elicits responses in a small population of trigeminal ganglion neurons (Fig.…”