Differential contribution of TRPM8 and TRPA1 channels to the cold sensitivity of somatic and visceral neurons

Resumen del póster presentado al International Workshop on Chronic Pain and Itch: Mechanisms and Circuits, celebrado en Alicante (España) del 20 al 22 de octubre de 2021.Thermal signals provide essential information for the operation of interoceptive and exteroceptive neural circuits. They are essential for triggering thermally-driven reflexes and conscious behaviors. A fraction of cutaneous and visceral sensory endings are activated by cold temperatures. In comparison to somatic (DRG and TG) neurons, very little is known about the cellular and molecular mechanisms underlying cold sensitivity of visceral vagal neurons. We used pharmacological, molecular and genetic tools for a side-by-side characterization of cold-sensitive (CS) neurons in adult mouse trigeminal (TG) and vagal ganglia (VG). We found that CS neurons are more abundant in VG than in TG. In both ganglia, sensitivity to cold varied widely, with activation thresholds spanning a range ~15 ºC. In both ganglia, cold sensitivity was enhanced by the potassium channel blocker 4-AP. About 2/3 of CS neurons in VG co-express TRPA1 markers and cold-evoked responses are severely blunted in Trpa1 KO mice, with little impact of TRPM8 deletion or pharmacological TRPM8 blockade. Consistent with this result, by qPCR, we detected lower levels of TRPM8 in VG compared to TG. The number of TRPM8-positive neurons was low in VG and restricted to the rostral jugular ganglion. Using fluorescent retrograde markers, be identified vagal neurons projecting to different viscera. Airway-innervating vagal neurons showed enhanced cold sensitivity and a higher functional expression of TRPA1 compared to neurons innervating the stomach wall. In contrast, the majority of CS TG neurons co-express TRPM8 markers and their cold sensitivity is reduced after TRPM8 deletion or pharmacological blockade. However, pharmacological or genetic reduction of TRPA1 showed that these channels also contribute to the activation of low-threshold TG cold sensitive neurons. In summary, we found that TRPA1 and TRPM8 channels show differential roles in the cold sensitivity of somatic and visceral vagal neurons.Supported by Ministerio de Ciencia e Innovación, PID2019-108194RB-100 co-financed by the European Regional Development Fund (ERDF), the “Severo Ochoa” Program for Centers of Excellence in R&D SEV-2017-0723 and the International PhD Fellowships Program “La Caixa”-Severo Ochoa, Call 2015” (KGB) and predoctoral fellowship BES-2017-080782 (PHO).Peer reviewe