Gandhi, A. R. | Search bioRxiv

bioRxiv2026

Trpv1+ sensory innervation of the salivary gland drives pain and supports saliva secretion

Sensory neurons have been increasingly recognized as vital contributors to deep tissue function. However, how these specialized neurons contribute to salivary gland function remains largely undefined. Here, we uncover a role for trigeminal somatosensory afferents in salivary gland perception and function using in situ-based classification, in vivo calcium imaging, behavioral assays, and targeted ablation. Retrograde labeling from the submandibular gland complex revealed substantial direct innervation from trigeminal neurons. Further categorization confirmed that Trpv1+ sensory neurons provided dense innervation of the Whartons ducts. TRPV1 agonist ductal infusion directly activated gland complex-associated neurons in the trigeminal ganglia and evoked a robust pain phenotype. Targeted Trpv1+ ablation disrupted Whartons ducts structure and dramatically reduced stimulated saliva volume. Our work provides the first evidence that Trpv1+ sensory neurons maintain salivary architecture and are necessary for stimulated saliva production, revealing a vital interoceptive role for direct trigeminal innervation in submandibular gland health.

physiology↗

bioRxiv2024

Intradental mechano-nociceptors serve as sentinels that prevent tooth damage

Pain is the anticipated output of the trigeminal sensory neurons that innervate the tooths vital interior1,2; however, the contribution of intradental neurons to healthy tooth sensation has yet to be defined. Here, we employ in vivo Ca2+ imaging to identify and define a population of myelinated high-threshold mechano-nociceptors (intradental HTMRs) that detect superficial structural damage of the tooth, produce pain, and initiate a jaw opening reflex. Intradental HTMRs remain inactive when direct forces are applied to the intact tooth but become responsive to forces when the structural integrity of the tooth is compromised, and the dentin or pulp is exposed. Their terminals collectively innervate the inner dentin through overlapping receptive fields, allowing them to monitor the superficial structures of the tooth. Indeed, intradental HTMRs detect superficial enamel damage and encode its degree, and their responses persist in the absence of either PIEZO2 or Nav1.83,4. As predicted, chemogenetic activation of intradental HTMRs results in a marked pain phenotype like that produced by systemic chemogenetic activation of nociceptors. Remarkably, optogenetic activation of intradental HTMRs triggers a rapid, jaw opening reflex via contraction of the digastric muscle. Taken together, our data indicate that intradental HTMRs serve as sentinels that guard against mechanical threats to the tooth; their activation not only triggers pain, but also results in physical tooth separation, which would prevent damage during mastication. Our work provides a new perspective of intradental neurons, highlighting their protective role, and illustrates the functional diversity of interoreceptors.

neuroscience↗