{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:10Z","timestamp":1792790350299,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,15]]},"group-title":"Neuroscience","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["K00NS124190"],"award-info":[{"award-number":["K00NS124190"]}]},{"name":"National Institutes of Health","award":["F32NS128392"],"award-info":[{"award-number":["F32NS128392"]}]},{"name":"National Institutes of Health","award":["K99NS134965"],"award-info":[{"award-number":["K99NS134965"]}]},{"name":"National Institutes of Health","award":["T32NS082128"],"award-info":[{"award-number":["T32NS082128"]}]},{"name":"National Institutes of Health","award":["RF1NS131165"],"award-info":[{"award-number":["RF1NS131165"]}]},{"name":"National Institutes of Health","award":["R61NS126026"],"award-info":[{"award-number":["R61NS126026"]}]},{"name":"American Neuromuscular Foundation","award":["Development Grant"],"award-info":[{"award-number":["Development Grant"]}],"id":[{"id":"https:\/\/ror.org\/00jgn6j98","id-type":"ROR","asserted-by":"crossref"}]},{"name":"PhRMA Foundation","award":["Postdoctoral Fellowship in Drug Discovery 1335819"],"award-info":[{"award-number":["Postdoctoral Fellowship in Drug Discovery 1335819"]}],"id":[{"id":"https:\/\/ror.org\/029sjzg14","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Parkinson's Foundation","award":["Summer Student Fellowship"],"award-info":[{"award-number":["Summer Student Fellowship"]}],"id":[{"id":"https:\/\/ror.org\/05mx85j86","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Genetically Engineered Mouse Models (GEMM) Core at the University of Arizona","award":["Pilot Grant"],"award-info":[{"award-number":["Pilot Grant"]}],"id":[{"id":"https:\/\/ror.org\/03m2x1q45","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,15]]},"abstract":"<jats:p>\n                  Pain is among the most prevalent and disabling nonmotor symptoms of Parkinson\u2019s disease (PD), yet its mechanisms remain poorly defined and effective treatments are limited. Safinamide is one of the few drugs reported to improve pain in PD, but the mechanism underlying this effect is unknown. Here, we show that nigrostriatal neurodegeneration produces persistent hyperexcitability of primary sensory neurons associated with dysregulation of the voltage-gated sodium channel Na\n                  <jats:sub>V<\/jats:sub>\n                  1.7. In a brain-restricted 6-hydroxydopamine (6-OHDA) model, small-diameter dorsal root ganglion (DRG) neurons exhibited increased sodium current density and altered voltage-dependent inactivation, with the excess current eliminated by selective Na\n                  <jats:sub>V<\/jats:sub>\n                  1.7 blockade. Safinamide directly inhibited a Na\n                  <jats:sub>V<\/jats:sub>\n                  1.7-dependent component of sensory neuron sodium current and reversed established pain-like behaviors. Pharmacological disruption of Na\n                  <jats:sub>V<\/jats:sub>\n                  1.7 regulation by collapsin response mediator protein 2 (CRMP2) normalized DRG hyperexcitability and reversed mechanical and thermal hypersensitivity, whereas genetic disruption of the Na\n                  <jats:sub>V<\/jats:sub>\n                  1.7 CRMP2 regulatory sequence prevented the development of 6-OHDA-induced pain-like behaviors for up to 30 weeks despite preservation of the Parkinsonian motor phenotype. Transcriptomic profiling of human PD DRGs revealed limited global transcriptional remodeling with selective alterations in genes associated with sensory neuron excitability. Together, these findings demonstrate that dopaminergic neurodegeneration initiated within the brain is sufficient to drive persistent peripheral sensory neuron dysfunction and identify CRMP2-dependent regulation of Na\n                  <jats:sub>V<\/jats:sub>\n                  1.7 as a therapeutic target for Parkinsonian pain.\n                <\/jats:p>","DOI":"10.64898\/2026.09.09.750469","type":"posted-content","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:50:20Z","timestamp":1789519820000},"source":"Crossref","is-referenced-by-count":1,"title":["Na\n                  <sub>V<\/sub>\n                  1.7-dependent peripheral sensitization drives chronic pain in Parkinson\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6675-4820","authenticated-orcid":false,"given":"Tyler S.","family":"Nelson","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi K.","family":"Grabus","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather N.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Calderon-Rivera","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Loya-Lopez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erick J.","family":"Rodriguez-Palma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaina L.","family":"Waters","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eslam","family":"Elhanafy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie I.","family":"Shiers","sequence":"additional","affiliation":[{"name":"University of Texas at Dallas, School of Behavioral and Brain Sciences, Department of Neuroscience, Center for Advanced Pain Studies, Richardson, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishwarya","family":"Sankaranarayanan","sequence":"additional","affiliation":[{"name":"University of Texas at Dallas, School of Behavioral and Brain Sciences, Department of Neuroscience, Center for Advanced Pain Studies, Richardson, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Gomez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-6221","authenticated-orcid":false,"given":"Theodore J.","family":"Price","sequence":"additional","affiliation":[{"name":"University of Texas at Dallas, School of Behavioral and Brain Sciences, Department of Neuroscience, Center for Advanced Pain Studies, Richardson, Texas, 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