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Here, we demonstrate that skeletal muscle hyperexcitability is sufficient to initiate a persistent pain state independent of inflammation, nerve injury, or overt tissue damage. Using complementary pharmacological and genetic models of myotonia resulting from loss of the voltage-gated skeletal muscle chloride channel ClC-1 function, we show that transient and chronic myotonia produce robust mechanical, thermal, and cold hypersensitivity, as well as spontaneous pain-like behavior. Notably, pain-like behaviors induced by transient myotonia persist long after overt motor symptoms have resolved, suggesting that a transient episode of muscle hyperexcitability is sufficient to trigger prolonged alterations in nociceptive processing. Physiological recordings revealed altered excitability of dorsal root ganglion and superficial dorsal horn neurons and enhanced sensory-evoked activity in the parabrachial nucleus, indicating altered nociceptive processing across multiple levels of the pain neuraxis. Transient myotonia increased total sodium current density in sensory neurons, with a shift toward a greater tetrodotoxin-resistant current fraction. Pharmacological inhibition with the Na\n                  <jats:sub>V<\/jats:sub>\n                  1.8-directed analgesic Suzetrigine markedly attenuated pain-like behaviors in both models of myotonia. Together, these findings establish a link between myotonia and persistent alterations in nociceptive processing and identify Na\n                  <jats:sub>V<\/jats:sub>\n                  1.8-directed analgesia as a promising therapeutic strategy for myotonia-associated pain.\n                <\/jats:p>","DOI":"10.1101\/2024.06.19.599732","type":"posted-content","created":{"date-parts":[[2024,6,23]],"date-time":"2024-06-23T03:00:14Z","timestamp":1719111614000},"source":"Crossref","is-referenced-by-count":0,"title":["Myotonic Muscle Activity Drives a Persistent Pain State Responsive to Na\n                  <sub>V<\/sub>\n                  1.8-directed Analgesics"],"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 32610, 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 32610, 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 32610, 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 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuel","family":"Loeza-Alcocer","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge B.","family":"Pineda-Farias","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narges","family":"Pachenari","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, 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 32610, 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 32610, 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 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paz","family":"Duran","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Gold","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9066-2969","authenticated-orcid":false,"given":"Rajesh","family":"Khanna","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 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