{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:51:45Z","timestamp":1768513905540,"version":"3.49.0"},"posted":{"date-parts":[[2024,7,16]]},"group-title":"Neuroscience","reference-count":39,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The pathology of diabetic small fiber neuropathy, characterized by neuropathic pain and axon degeneration, develops locally within the skin during the stages of obesity and pre-diabetes. However, the initiation and progression of morphological and functional abnormalities in skin sensory nerves remains elusive. To address this, we utilized ear skin from mice with diet-induced obesity (DIO), the mouse models for obesity and pre-type 2 diabetes. We evaluated pain-associated wiping behavior and conducted\n                  <jats:italic>ex vivo<\/jats:italic>\n                  live Ca\n                  <jats:sup>2+<\/jats:sup>\n                  imaging of the DIO ear skin to detect sensory hypersensitivity. Our findings reveal sensory hypersensitivity in skin nociceptive axons followed by axon degeneration. Further mechanistic analysis identified keratinocytes as a major source of nerve growth factor (NGF) in DIO skin, which locally sensitizes nociceptors through NGF-mediated signaling. Indeed, the local inactivation of NGF and its receptor TrkA-mediated downstream signaling, including the phosphoinositide 3-kinases (PI3K) pathway, suppresses sensory hypersensitivity in DIO skin. Thus, targeting these local interactions between keratinocytes and nociceptors offers a therapeutic strategy for managing neuropathic pain, avoiding the adverse effects associated with systemic interventions.\n                <\/jats:p>","DOI":"10.1101\/2024.07.12.603316","type":"posted-content","created":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T21:05:20Z","timestamp":1721163920000},"source":"Crossref","is-referenced-by-count":0,"title":["Local keratinocyte-nociceptor interactions enhance obesity-mediated small fiber neuropathy via NGF-TrkA-PI3K signaling axis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7769-4587","authenticated-orcid":false,"given":"Yuta","family":"Koui","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0788-9264","authenticated-orcid":false,"given":"Shuxuan","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9750-7718","authenticated-orcid":false,"given":"Xinzhong","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9084-4922","authenticated-orcid":false,"given":"Yoh-suke","family":"Mukouyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024071805350455000_2024.07.12.603316v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0092-1"},{"key":"2024071805350455000_2024.07.12.603316v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2011.137"},{"key":"2024071805350455000_2024.07.12.603316v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1529-8027.2012.00420.x"},{"key":"2024071805350455000_2024.07.12.603316v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2014.03.022"},{"key":"2024071805350455000_2024.07.12.603316v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-0102(02)00033-0"},{"key":"2024071805350455000_2024.07.12.603316v1.6","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn093"},{"key":"2024071805350455000_2024.07.12.603316v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22728"},{"key":"2024071805350455000_2024.07.12.603316v1.8","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.10.2615"},{"key":"2024071805350455000_2024.07.12.603316v1.9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0118134"},{"key":"2024071805350455000_2024.07.12.603316v1.10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92117"},{"key":"2024071805350455000_2024.07.12.603316v1.11","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.13771"},{"key":"2024071805350455000_2024.07.12.603316v1.12","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2021.0278"},{"key":"2024071805350455000_2024.07.12.603316v1.13","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics11020165"},{"key":"2024071805350455000_2024.07.12.603316v1.14","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.12650"},{"key":"2024071805350455000_2024.07.12.603316v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.06.016"},{"key":"2024071805350455000_2024.07.12.603316v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2008.08.002"},{"key":"2024071805350455000_2024.07.12.603316v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.12.011"},{"key":"2024071805350455000_2024.07.12.603316v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-18581-7"},{"key":"2024071805350455000_2024.07.12.603316v1.19","doi-asserted-by":"publisher","DOI":"10.1186\/s41232-017-0042-9"},{"key":"2024071805350455000_2024.07.12.603316v1.20","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-023-03741-1"},{"key":"2024071805350455000_2024.07.12.603316v1.21","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20221687"},{"key":"2024071805350455000_2024.07.12.603316v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7571-6_1"},{"key":"2024071805350455000_2024.07.12.603316v1.23","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S247472"},{"key":"2024071805350455000_2024.07.12.603316v1.24","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S89061"},{"key":"2024071805350455000_2024.07.12.603316v1.25","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-072116-031121"},{"key":"2024071805350455000_2024.07.12.603316v1.26","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22052589"},{"key":"2024071805350455000_2024.07.12.603316v1.27","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.38869"},{"key":"2024071805350455000_2024.07.12.603316v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2009.11.022"},{"key":"2024071805350455000_2024.07.12.603316v1.29","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.48.2.501"},{"key":"2024071805350455000_2024.07.12.603316v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00908-X"},{"key":"2024071805350455000_2024.07.12.603316v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/35082088"},{"key":"2024071805350455000_2024.07.12.603316v1.32","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000012894"},{"key":"2024071805350455000_2024.07.12.603316v1.33","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.58625"},{"key":"2024071805350455000_2024.07.12.603316v1.34","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.65987"},{"key":"2024071805350455000_2024.07.12.603316v1.35","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.31684"},{"key":"2024071805350455000_2024.07.12.603316v1.36","doi-asserted-by":"publisher","DOI":"10.1126\/science.1228258"},{"key":"2024071805350455000_2024.07.12.603316v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.223"},{"key":"2024071805350455000_2024.07.12.603316v1.38","doi-asserted-by":"publisher","DOI":"10.3791\/57406"},{"key":"2024071805350455000_2024.07.12.603316v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.50"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.07.12.603316","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:43:03Z","timestamp":1768459383000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.07.12.603316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,16]]},"references-count":39,"URL":"https:\/\/doi.org\/10.1101\/2024.07.12.603316","relation":{},"subject":[],"published":{"date-parts":[[2024,7,16]]},"subtype":"preprint"}}