{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T19:27:24Z","timestamp":1786735644369,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,12]]},"group-title":"Physiology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01DE032345"],"award-info":[{"award-number":["R01DE032345"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["F31DE034282"],"award-info":[{"award-number":["F31DE034282"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32DC000011"],"award-info":[{"award-number":["T32DC000011"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>in situ<\/jats:italic>\n                  -based classification,\n                  <jats:italic>in vivo<\/jats:italic>\n                  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\n                  <jats:italic>Trpv1<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  sensory neurons provided dense innervation of the Wharton\u2019s ducts. TRPV1 agonist ductal infusion directly activated gland complex-associated neurons in the trigeminal ganglia and evoked a robust pain phenotype. Targeted\n                  <jats:italic>Trpv1<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  ablation disrupted Wharton\u2019s duct\u2019s structure and dramatically reduced stimulated saliva volume. Our work provides the first evidence that\n                  <jats:italic>Trpv1<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  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.\n                <\/jats:p>","DOI":"10.64898\/2026.08.06.743081","type":"posted-content","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T14:25:12Z","timestamp":1786544712000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>\n                    Trpv1\n                    <sup>+<\/sup>\n                  <\/i>\n                  sensory innervation of the salivary gland drives pain and supports saliva secretion"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1909-4398","authenticated-orcid":false,"given":"Deanna N.","family":"Cannizzaro","sequence":"first","affiliation":[{"name":"Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Amorim","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romy E.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6587-1286","authenticated-orcid":false,"given":"Kayla M.","family":"Moehn","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshayapriya","family":"Saravanan","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iva","family":"Vesela","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akash R.","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7547-6375","authenticated-orcid":false,"given":"Isabelle M.A.","family":"Lombaert","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5619-1078","authenticated-orcid":false,"given":"Joshua J.","family":"Emrick","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081411300935000_2026.08.06.743081v1.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0901507106"},{"key":"2026081411300935000_2026.08.06.743081v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb2751"},{"key":"2026081411300935000_2026.08.06.743081v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.11.027"},{"key":"2026081411300935000_2026.08.06.743081v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.11.028"},{"key":"2026081411300935000_2026.08.06.743081v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/cne.25148"},{"key":"2026081411300935000_2026.08.06.743081v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114665"},{"key":"2026081411300935000_2026.08.06.743081v1.7","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0328-21.2022"},{"key":"2026081411300935000_2026.08.06.743081v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2026.01.021"},{"key":"2026081411300935000_2026.08.06.743081v1.9","doi-asserted-by":"publisher","DOI":"10.1111\/iej.70129"},{"key":"2026081411300935000_2026.08.06.743081v1.10","doi-asserted-by":"publisher","DOI":"10.1007\/s10266-025-01092-7"},{"key":"2026081411300935000_2026.08.06.743081v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.116017"},{"key":"2026081411300935000_2026.08.06.743081v1.12","doi-asserted-by":"publisher","DOI":"10.1177\/0022034520941837"},{"key":"2026081411300935000_2026.08.06.743081v1.13","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00015.2021"},{"key":"2026081411300935000_2026.08.06.743081v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/stem.2455"},{"key":"2026081411300935000_2026.08.06.743081v1.15","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.41859"},{"key":"2026081411300935000_2026.08.06.743081v1.16","doi-asserted-by":"publisher","DOI":"10.4081\/cp.2019.1119"},{"key":"2026081411300935000_2026.08.06.743081v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2005.08.012"},{"key":"2026081411300935000_2026.08.06.743081v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2017.12.015"},{"key":"2026081411300935000_2026.08.06.743081v1.19","doi-asserted-by":"publisher","DOI":"10.3791\/3074"},{"key":"2026081411300935000_2026.08.06.743081v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2009.10.006"},{"key":"2026081411300935000_2026.08.06.743081v1.21","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001911"},{"key":"2026081411300935000_2026.08.06.743081v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.07.024"},{"key":"2026081411300935000_2026.08.06.743081v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.10.028"},{"key":"2026081411300935000_2026.08.06.743081v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2023.100415"},{"key":"2026081411300935000_2026.08.06.743081v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1455"},{"key":"2026081411300935000_2026.08.06.743081v1.26","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-24-2375"},{"key":"2026081411300935000_2026.08.06.743081v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2008.12.014"},{"key":"2026081411300935000_2026.08.06.743081v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2009.02.002"},{"key":"2026081411300935000_2026.08.06.743081v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.10.021"},{"key":"2026081411300935000_2026.08.06.743081v1.30","doi-asserted-by":"publisher","DOI":"10.3390\/ph9030047"},{"key":"2026081411300935000_2026.08.06.743081v1.31","doi-asserted-by":"publisher","DOI":"10.46747\/cfp.6908531"},{"key":"2026081411300935000_2026.08.06.743081v1.32","unstructured":"Hammett, J.T. , and Walker, C. (2026). Sialolithiasis. In StatPearls."},{"key":"2026081411300935000_2026.08.06.743081v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2024.122954"},{"key":"2026081411300935000_2026.08.06.743081v1.34","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.80139"},{"key":"2026081411300935000_2026.08.06.743081v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2014.11.042"},{"key":"2026081411300935000_2026.08.06.743081v1.36","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-6-94"},{"key":"2026081411300935000_2026.08.06.743081v1.37","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6451-10.2011"},{"key":"2026081411300935000_2026.08.06.743081v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2024.103208"},{"key":"2026081411300935000_2026.08.06.743081v1.39","doi-asserted-by":"publisher","DOI":"10.1101\/2021.11.10.468116"},{"key":"2026081411300935000_2026.08.06.743081v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(84)90346-9"},{"key":"2026081411300935000_2026.08.06.743081v1.41","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1046\/j.1439-0264.2003.00493.x","article-title":"Distribution of sympathetic and afferent neurons innervating the submandibular gland in the sheep","volume":"32","year":"2003","journal-title":"Anat Histol Embryol"},{"key":"2026081411300935000_2026.08.06.743081v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(80)90092-X"},{"key":"2026081411300935000_2026.08.06.743081v1.43","unstructured":"S., S. (1983). Physiology of mechanical senses of the oral strucutres. In Frontiers of Oral Physiology Oral Sensory Mechanisms, K. Y., ed. pp. 1\u201332."},{"key":"2026081411300935000_2026.08.06.743081v1.44","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/BF00492515","article-title":"CGRP-immunoreactive sensory nerve fibers in the submandibular gland of the rat","volume":"91","year":"1989","journal-title":"Histochemistry"},{"key":"2026081411300935000_2026.08.06.743081v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(88)90110-8"},{"key":"2026081411300935000_2026.08.06.743081v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(82)90400-0"},{"key":"2026081411300935000_2026.08.06.743081v1.47","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-013-1691-x"},{"key":"2026081411300935000_2026.08.06.743081v1.48","doi-asserted-by":"publisher","DOI":"10.1002\/jemt.21090"},{"key":"2026081411300935000_2026.08.06.743081v1.49","doi-asserted-by":"publisher","DOI":"10.1177\/0022034510366841"},{"key":"2026081411300935000_2026.08.06.743081v1.50","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.28147"},{"key":"2026081411300935000_2026.08.06.743081v1.51","doi-asserted-by":"publisher","DOI":"10.4196\/kjpp.2014.18.6.525"},{"key":"2026081411300935000_2026.08.06.743081v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.09.008"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.08.06.743081","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T18:30:17Z","timestamp":1786732217000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.08.06.743081"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":52,"URL":"https:\/\/doi.org\/10.64898\/2026.08.06.743081","relation":{},"subject":[],"published":{"date-parts":[[2026,8,12]]},"subtype":"preprint"}}