Piezo1-pannexin-1-P2X3 axis in odontoblasts and neurons mediates sensory transduction in dentinal sensitivity

Abstract

According to the “hydrodynamic theory,” dentinal pain or sensitivity is caused by dentinal fluid movement following the application of various stimuli to the dentin surface. Recent convergent evidence in Vitro has shown that plasma membrane deformation, mimicking dentinal fluid movement, activates mechanosensitive transient receptor potential (TRP)/Piezo channels in odontoblasts, with the Ca2+ signal eliciting the release of ATP from pannexin-1 (PANX-1). The released ATP activates the P2X3 receptor, which generates and propagates action potentials in the intradental Aδ afferent neurons. Thus, odontoblasts act as sensory receptor cells, and odontoblast-neuron signal communication established by the TRP/Piezo channel-PANX-1-P2X3 receptor complex may describe the mechanism of the sensory transduction sequence for dentinal sensitivity. To determine whether odontoblast-neuron communication and odontoblasts acting as sensory receptors are essential for generating dentinal pain, we evaluated nociceptive scores by analyzing behaviors evoked by dentinal sensitivity in conscious Wistar rats and Cre-mediated transgenic mouse models. In the dentin-exposed group, treatment with a bonding agent on the dentin surface, as well as systemic administration of A-317491 (P2X3 receptor antagonist), mefloquine and 10PANX (non-selective and selective PANX-1 antagonists), GsMTx-4 (selective Piezo1 channel antagonist), and HC-030031 (selective TRPA1 channel antagonist), but not HC-070 (selective TRPC5 channel antagonist), significantly reduced nociceptive scores following cold water (0.1 ml) stimulation of the exposed dentin surface of the incisors compared to the scores of rats without local or systemic treatment. When we applied cold water stimulation to the exposed dentin surface of the lower first molar, nociceptive scores in the rats with systemic administration of A-317491, 10PANX, and GsMTx-4 were significantly reduced compared to those in the rats without systemic treatment. Dentin-exposed mice, with somatic odontoblast-specific depletion, also showed significant reduction in the nociceptive scores compared to those of Cre-mediated transgenic mice, which did not show any type of cell deletion, including odontoblasts. In the odontoblast-eliminated mice, P2X3 receptor-positive A-neurons were morphologically intact. These results indicate that neurotransmission between odontoblasts and neurons mediated by the Piezo1/TRPA1-pannexin-1-P2X3 receptor axis is necessary for the development of dentinal pain. In addition, odontoblasts are necessary for sensory transduction to generate dentinal sensitivity as mechanosensory receptor cells.

Immunolocalization of the mechanogated ion channels PIEZO1 and PIEZO2 in human and mouse dental pulp and periodontal ligament

“…In mice, both odontoblasts and fibroblasts of the periodontal ligament are immunoreactive for PIEZO1 and PIEZO2. This is in agreement with previous studies reporting the presence of PIEZO1 (Mousawi et al, 2020; Ohyama et al, 2022; Sun et al, 2022) and PIEZO2 (Khatibi Shahidi et al, 2015) in murine odontoblasts and the occurrence of PIEZO1 (Jiang et al, 2021; Jin et al, 2015) and PIEZO2 (Gao et al, 2017) in the periodontal ligament.…”

“…Data on the occurrence and role of PIEZOs in teeth are scarce. Functional PIEZO1 is expressed in cultured human pulp cells (Mousawi et al, 2020; Ohyama et al, 2022; Sun et al, 2022) and periodontal ligament fibroblasts (Jiang et al, 2021; Jin et al, 2015; Lukacs et al, 2023), whereas PIEZO2 is ubiquitously expressed in mouse odontoblasts (Khatibi Shahidi et al, 2015) and periodontal cell lines (Gao et al, 2017; Lukacs et al, 2023).…”

Nociceptor mechanisms underlying pain and bone remodeling via orthodontic forces: toward no pain, big gain

“…Instead, Piezo1 expressed in non-neuronal cells may indirectly contribute to pain. For example, Piezo1 expressed in keratinocytes regulates mechanotransduction ( 109 ) and, when expressed in odontoblasts, it may mediate nociceptive signaling through the release of ATP by the activation of P2X3 in sensory neurons ( 110 ). The activation of Piezo1 in human periodontal ligament cells by Yoda1 increases intracellular Ca 2+ and extracellular ATP ( 55 ).…”

PIEZO Ion Channels in Cardiovascular Functions and Diseases

“…Some preferential coupling however is found in different cell types. PIEZO1 coupling to pannexin and ATP release has been reported in many cell types, including ECs to enhance NO production, 71 lung alveolar epithelial type I cells to promote surfactant secretion, 190 odontoblasts to participate in dentinal sensitivity, 191 and cholangiocytes to contribute to bile secretion. 192 Likewise, the PIEZO1-YAP axis has recently emerged as an important pathway common to different cell types including cardiovascular cells.…”