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ResearchIn-Press PreviewMuscle biologyNeuroscience Open Access | 10.1172/JCI198055

Myotonic Muscle Activity Drives a Persistent Pain State Responsive to NaV1.8-directed Analgesics

Tyler S. Nelson,1 Aida Calderon-Rivera,1 Heather N. Allen,1 Alaina L Waters,1 Emanuel Loeza-Alcocer,2 Jorge B. Pineda-Farias,2 Narges Pachenari,2 Santiago Loya-Lopez,1 Kimberly Gomez,1 Erick J. Rodriguez-Palma,1 Paz Duran,3 Michael S. Gold,2 and Rajesh Khanna1

1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

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1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

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1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

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1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

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1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

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1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

Find articles by Pineda-Farias, J. in: PubMed | Google Scholar

1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

Find articles by Pachenari, N. in: PubMed | Google Scholar

1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

Find articles by Loya-Lopez, S. in: PubMed | Google Scholar

1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

Find articles by Gomez, K. in: PubMed | Google Scholar

1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

Find articles by Rodriguez-Palma, E. in: PubMed | Google Scholar

1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

Find articles by Duran, P. in: PubMed | Google Scholar

1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

Find articles by Gold, M. in: PubMed | Google Scholar

1Department of Pharmacology and Therapeutics, McKnight Brain Institute, and Center for Advanced Pain Therapeutics and Research (CAPToR), College of Medicine, University of Florida, Gainesville, United States of America

2Department of Neurobiology, and Pittsburgh Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Department of Molecular Pathobiology, College of Dentistry, New York University, New York, United States of America

Find articles by Khanna, R. in: PubMed | Google Scholar |

Published September 8, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI198055.
Copyright © 2026, Nelson et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 8, 2026 - Version history
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Abstract

Pain is a common and disabling feature of myotonic disorders, yet its biological basis remains poorly understood and no targeted analgesic therapies currently exist. 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 NaV1.8-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 NaV1.8-directed analgesia as a promising therapeutic strategy for myotonia-associated pain.

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