Involvement of TRPV4 ionotropic channel in tongue mechanical hypersensitivity in dry-tongue rats

Abstract

Although xerostomia can cause persistent oral pain, the mechanisms underlying such pain are not well understood. To evaluate whether a phosphorylated p38 (pp38)-TRPV4 mechanism in trigeminal ganglion (TG) neurons has a role in mechanical hyperalgesia of dry tongue, a rat model of dry tongue was used to study the nocifensive reflex and pp38 and TRPV4 expression in TG neurons. The head-withdrawal reflex threshold for mechanical stimulation of the tongue was significantly lower in dry-tongue rats than in sham rats. The numbers of TRPV4-and pp38immunoreactive cells in the TG were significantly higher in dry-tongue rats than in sham rats. Many TRPV4-IR cells were also pp38-immunoreactive. The number of TRPV1-IR cells was unchanged in the TG after induction of tongue dryness. Local injection of a TRPV4 blocker attenuated tongue mechanical hypersensitivity in dry-tongue rats. Intraganglionic injection of a selective p38 MAP kinase inhibitor eliminated tongue hypersensitivity in dry-tongue rats and suppressed TRPV4 expression in TG neurons. The present findings suggest that TRPV4 activation via p38 phosphorylation in TG neurons is involved in mechanical hypersensitivity associated with dry tongue. These mechanisms may have a role in pain associated with xerostomia. Dry-tongue rat modelRats were anesthetized in a plastic chamber with 2% isoflurane (Mylan, Canonsburg, PA, USA) in normal room air. The tongue was gently extended out of the mouth and left exposed to room air for 2 h daily for 7 days (dry-tongue rats). Sham rats were anesthetized in the same manner, but dry tongue was not induced.

A perspective from experimental studies of burning mouth syndrome

“…The pERK-pGluR1 cascade was involved in the central neuronal mechanism of drying tongue pain in the trigeminal spinal nucleus caudalis (Vc). Chen et al [68] studied the peripheral neuronal mechanism in dry mouth model rats and suggested that activation of TRPV4 via pp38 in trigeminal ganglion neurons is involved in mechanical hyperalgesia.…”

Oxytocin-Dependent Regulation of TRPs Expression in Trigeminal Ganglion Neurons Attenuates Orofacial Neuropathic Pain following Infraorbital Nerve Injury in Rats

“…TRPV4 is activated by warm temperature (>27 • C) and extracellular osmolarity, indicating its role as a mechanosensitive channel [15]. Peripheral TRPV4 antagonism suppresses xerostomia-induced tongue mechanical allodynia in rodents [16]. In some studies, changes in the TRPV1 and TRPV4 expression in the primary nociceptive neurons following trigeminal nerve injury or orofacial trauma were reported to be involved in orofacial pain hypersensitivity [17][18][19].…”

Pharmacological activation of transient receptor potential vanilloid 4 promotes triggering of the swallowing reflex in rats

“…S, seconds. (Hamamoto et al, 2008;Foote et al, 2022), lungs (Fernández-Fernández et al, 2008, cornea (Mergler et al, 2011), esophagus (Mihara et al, 2011;Ueda et al, 2011), stomach (Mihara et al, 2016), bladder (Birder et al, 2007;Janssen et al, 2011), oral mucosa (Nakatsuka and Iwai, 2009;Moayedi et al, 2022;Yahya et al, 2022), odontoblasts (Egbuniwe et al, 2014), taste buds (Matsumoto et al, 2019), hippocampal neurons (Shibasaki et al, 2007), dorsal root ganglia (Cao et al, 2009;Liu et al, 2010;Lechner et al, 2011), trigeminal (Denadai-Souza et al, 2012Chen et al, 2013Chen et al, , 2014Chen et al, , 2020, and vagal ganglia (Bonvini et al, 2016), and nerve fibers in the dental pulp (Bakri et al, 2018). Here we report TRPV4 on nerve fibers in SLN-innervated swallowing-related regions.…”

“…Transient receptor potential vanilloid 4 is localized in TG (Denadai-Souza et al, 2012;Chen et al, 2013Chen et al, , 2014Chen et al, , 2020; therefore, we used TG sections as a positive control for the anti-TRPV4 antibody (Supplementary Figure 1). As a negative control, the sections were incubated with a universal negative control reagent (Cat # ADI-950-231-0025; Enzo Life Sciences, Inc., Farmingdale, NY) instead of the primary antibody (Supplementary Figure 1).…”