Abstract
Pain is the anticipated output of the trigeminal sensory neurons that innervate the tooth's vital interior (1,2) ; however, the contribution of intradental neurons to healthy tooth sensation has yet to be defined. Here, we employ in vivo Ca (2+) 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 Na (v) 1.8 (3,4) . 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.