Piezo channels are mechanosensitive ion channels. Piezo1 is primarily expressed in nonsensory tissues, whereas Piezo2 is predominantly found in sensory tissues, including dorsal root ganglion (DRG) neurons. However, a recent study demonstrated the intracellular calcium response to Yoda1, a selective Piezo1 agonist, in trigeminal ganglion (TG) neurons. Herein, we investigate the expression of Piezo1 mRNA and protein in mouse and human DRG neurons and the activation of Piezo1 via calcium influx by Yoda1. Yoda1 induces inward currents mainly in small- (<25 μm) and medium-sized (25–35 μm) mouse DRG neurons. The Yoda1-induced Ca²⁺ response is inhibited by cationic channel blocker, ruthenium red and cationic mechanosensitive channel blocker, GsMTx4. To confirm the specific inhibition of Piezo1, we performed an adeno-associated virus serotype 2/5 (AAV2/5)-mediated delivery of short hairpin RNA (shRNA) into mouse DRG neurons. AAV2/5 transfection downregulates piezo1 mRNA expression and reduces Ca²⁺ response by Yoda1. Piezo1 also shows physiological functions with transient receptor potential vanilloid 1 (TRPV1) in the same DRG neurons and is regulated by the activation of TRPV1 in mouse DRG sensory neurons. Overall, we found that Piezo1 has physiological functions in DRG neurons and that TRPV1 activation inhibits an inward current induced by Yoda1.

The tooth has an unusual sensory system that converts external stimuli predominantly into pain, yet its sensory afferents in teeth demonstrate cytochemical properties of non-nociceptive neurons. This review summarizes the recent knowledge underlying this paradoxical nociception, with a focus on the ion channels involved in tooth pain. The expression of temperature-sensitive ion channels has been extensively investigated because thermal stimulation often evokes tooth pain. However, temperature-sensitive ion channels cannot explain the sudden intense tooth pain evoked by innocuous temperatures or light air puffs, leading to the hydrodynamic theory emphasizing the microfluidic movement within the dentinal tubules for detection by mechanosensitive ion channels. Several mechanosensitive ion channels expressed in dental sensory systems have been suggested as key players in the hydrodynamic theory, and TRPM7, which is abundant in the odontoblasts, and recently discovered PIEZO receptors are promising candidates. Several ligand-gated ion channels and voltage-gated ion channels expressed in dental primary afferent neurons have been discussed in relation to their potential contribution to tooth pain. In addition, in recent years, there has been growing interest in the potential sensory role of odontoblasts; thus, the expression of ion channels in odontoblasts and their potential relation to tooth pain is also reviewed.

Local anesthetics (LAs) can completely block nociception by inhibiting voltage-gated sodium channels (VGSCs), and thus, blocking action potentials (APs) within sensory neurons. As one of the several LAs, eugenol is used for dental pain treatment. It reportedly features multiple functions in regulating diverse ion channels. This study aimed to investigate the long-lasting analgesic effect of eugenol alone, as well as that of the combination of eugenol as a noxious-heat-sensitive transient receptor potential vanilloid 1 (TRPV1) channel agonist and a permanently charged sodium channel blocker (QX-314), on neuronal excitability in trigeminal ganglion (TG) neurons. Eugenol alone increased inward current in a dose-dependent manner in capsaicin-sensitive TG neurons. Eugenol also inhibited the VGSC current and AP. These effects were reversed through wash-out. The combination of eugenol and QX-314 was evaluated in the same manner. The combination completely inhibited the VGSC current and AP. However, these effects were not reversed and were continuously blocked even after wash-out. Taken together, our results suggest that, in contrast to the effect of eugenol alone, the combination of eugenol and QX-314 irreversibly and selectively blocked VGSCs in TG neurons expressing TRPV1.

Peripheral nerve injury can lead to chronic mechanical hypersensitivity, yet the severity and persistence of pain are strongly influenced by the extent of axonal damage. Notably, partial sciatic nerve crush injury (PCI) produces persistent tactile hypersensitivity despite a less severe anatomical insult than full crush injury, yet the identity and postinjury state of the fibers that persist after PCI remain unclear. To define sensory neuron populations contributing to PCI-induced tactile hypersensitivity, we combined fiber-specific transgenic labeling (Thy1-YFP for Aβ mechanoreceptors and Nav1.8-tdTomato for nociceptors) with pharmacological silencing using QX-314 coapplied with transient receptor potential vanilloid 1 (TRPV1) (capsaicin) and toll-like receptor 5 (flagellin) agonists to selectively manipulate fiber subtypes. At day 7 after PCI, Nav1.8 ⁺ nociceptive terminals were still detectable in the hind paw. On day 30, acute silencing of TRPV1 ⁺ afferents transiently reduced mechanical hypersensitivity, indicating nociceptor activity in its maintenance. Whole-cell patch clamp recordings of retrogradely labeled dorsal root ganglia neurons showed that remaining medium-diameter neurons exhibited reduced rheobase and increased action potential firings in response to step current injections. Besides, electrical stimulation of nociceptive fibers increased phosphorylated extracellular signal-regulated protein kinase expression in the spinal dorsal horn, indicating enhanced nociceptive signaling after PCI. Early ablation of TRPV1 ⁺ fibers with high-dose capsaicin during the degeneration phase prevented the subsequent development of long-term tactile hypersensitivity. Collectively, our results suggest that spared nociceptors after PCI remain sensitized even during nerve repair, driving long-term tactile hypersensitivity. Targeting these spared nociceptive fibers after nerve injury may offer a potential strategy for preventing chronic pain associated with traumatic nerve injury.

Pain often accompanies tissue injury and inflammation. However, in certain inflammatory contexts like periodontitis, nociceptive signaling is paradoxically suppressed. The mechanisms underlying this analgesic state remain poorly understood. Here, we investigated whether and how Porphyromonas gingivalis (Pg) interacts with sensory neurons to induce analgesia in models of inflammatory pain. Exposure to live Pg reversed inflammatory thermal and mechanical hypersensitivity without altering local inflammation or nerve innervation. This effect required direct physical contact mediated in part by an integrin α ₅ -FimA interface and gingipain protease activity and was not reproduced by heat-killed bacteria, protease-deficient mutants, or Pg-derived extracellular vesicles. At the neuronal level, Pg contact induced membrane hyperpolarization, reduced excitability of sensory neurons, and suppressed release of the nociceptive neuropeptide calcitonin gene-related peptide (CGRP). Proteomic and functional analyses identified downregulation of Fxyd2, a regulatory subunit of the Na ⁺ /K ⁺ -ATPase, linking altered ionic homeostasis to nociceptor silencing. These findings define a contact-dependent mechanism that actively suppresses peripheral pain signaling during inflammation.