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ResearchIn-Press PreviewEndocrinologyNeuroscience Open Access | 10.1172/JCI197345

Catecholamine-mediated release of miR-133a-3p from adipocytes regulates the onset of chronic primary pain

Nathaniel P. Hernandez,1 Jiegen Chen,1 Yiling Qian,1 Xin Zhang,1 Yaomin Wang,1 Brittney P. Ciszek,1 Xianglong Gao,1 Marguerita E. Klein,1 Yun-Ling Pai,2 Mohamad Karaky,3 Carolina B. Meloto,3 Francesca Montagna,3 Matt Kanke,4 Clair Crewe,2 Luda Diatchenko,3 Praveen Sethupathy,4 and Andrea G. Nackley1

1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

Find articles by Diatchenko, L. in: PubMed | Google Scholar |

1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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1Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, United States of America

3Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, McGill University, Montréal,, Canada

4Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, United States of America

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Published July 21, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI197345.
Copyright © 2026, Hernandez 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 July 21, 2026 - Version history
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Abstract

Chronic primary pain conditions (CPPCs), such as fibromyalgia and vestibulodynia, affect over 100 million Americans, predominantly women, and pose a substantial healthcare challenge. CPPCs arise from genetic and environmental factors that enhance catecholamine tone, potentially through miRNA dysregulation following catecholamine activation of beta-adrenergic receptors. Here, we identified miR-133a-3p as a biomarker of CPPC status and investigated its functions using in vivo and in vitro approaches. Plasma levels of miR-133a-3p were consistently downregulated in humans with ≥1 CPPC and in rat and mouse models of primary pain. Our data suggest that miR-133a-3p is packaged in extracellular vesicles that are secreted by adipocytes and trafficked to the spinal cord. Activation of adrenergic receptors on white adipocytes resulted in downregulation of miR-133a-3p which negatively regulated pain-related genes in the spinal cord, such as MAP3K3, which is critical for sensory neuron activation. Adipose-specific overexpression of miR-133a-3p in a mouse model of primary pain reversed mechanical hypersensitivity in both sexes. These findings implicate miR-133a-3p dysregulation in primary pain across conditions and species and establish its role in multi-site mechanical hypersensitivity. Further, miR-133a-3p overexpression shows therapeutic potential for the millions of individuals with CPPCs.

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