OSCR

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

Overview

Authors: Nathaniel P Hernandez1,2, Jiegen Chen1, Yiling Qian1, Xin Zhang1, Yaomin Wang1, Brittney P Ciszek1,3, Xianglong Gao1, Marguerita E Klein1, Yun-Ling Pai4, Mohamad Karaky5,6, Carolina Beraldo Meloto5, Francesca Montagna5, Matt Kanke7, Clair Crewe4, Luda Diatchenko5,6, Praveen Sethupathy7, Andrea G Nackley1,2
ORCID iDs: Luda Diatchenko
  1. Center for Translational Pain Medicine, Department of Anesthesiology, and
  2. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA
  3. WhiteCap Implant Institute, Herber City, Utah, USA
  4. Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
  5. Faculty of Medicine and Health Sciences, The Alan Edwards Centre for Research on Pain, and
  6. Faculty of Dental Medicine and Oral Health Sciences, Department of Anesthesia, McGill University, Montreal, Quebec, Canada
  7. Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, New York, USA
Institutions: Duke University (United States); Duke Medical Center (United States); Washington University in St. Louis (United States); McGill University (Canada); Cornell University (United States); New York State College of Veterinary Medicine (United States)
Journal: The Journal of clinical investigation, volume 136, issue 17, article e197345
Dates: received 26 June 2025; accepted 14 July 2026; published online 21 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1172/jci197345 · PMID 42479461 · PMCID PMC13528929 · OpenAlex W7169869670
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), rat (organism), pain (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials, Connectivity, Single-unit activity, calcium imaging
Keywords: Endocrinology, Neuroscience, Adipose tissue, Gene therapy, Pain
MeSH: Adipocytes*, Catecholamines*, Chronic Pain*, MicroRNAs*, Animals, Female, Humans, Male, Mice, Rats, Spinal Cord (* major topic)
Topic: Pain Mechanisms and Treatments (Physiology, Medicine), according to OpenAlex
Funding: National Institute of Neurological Disorders and Stroke (P01NS045685, F31NS130861, R01NS109541, R03NS106166); NINDS NIH HHS (R01 NS109541, F31 NS130861, P01 NS045685, R03 NS106166); NIDDK NIH HHS (P30 DK020579); NIGMS NIH HHS (T32 GM133352); National Institute of General Medical Sciences (T32GM133352); National Institute of Biomedical Imaging and Bioengineering (1R21EB035738); American Heart Association (23IPA1054013); National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020579); NIBIB NIH HHS (R21 EB035738)
Citations: not cited yet (Europe PMC); 98 references in the paper

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 β-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, negatively regulating 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 multisite mechanical hypersensitivity. Furthermore, miR-133a-3p overexpression shows therapeutic potential for the millions of individuals with CPPCs.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data availability

Values for all data points in graphs are reported in the Supporting Data Values file. Data are presented as mean ± SD, except for RNA-seq data. The RNA-seq data have been deposited in NCBI’s Gene Expression Omnibus under accession number GSE338452 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE338452). Full, uncropped Western blots (Figure 7, A and B, and Supplemental Figure 10) are available in the supplemental materials.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Authors: added Luda Diatchenko (0000-0002-1350-6727); removed Luda Diatchenko

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 17 authors, 5 keywords, 11 MeSH terms, 9 funders, 98 references.

Cite

This paper

Hernandez, N. P., Chen, J., Qian, Y., Zhang, X., Wang, Y., Ciszek, B. P., Gao, X., Klein, M. E., Pai, Y.-L., Karaky, M., Meloto, C. B., Montagna, F., Kanke, M., Crewe, C., Diatchenko, L., Sethupathy, P., & Nackley, A. G. (2026). Catecholamine-mediated release of miR-133a-3p from adipocytes regulates the onset of chronic primary pain. The Journal of clinical investigation, 136(17), e197345. https://doi.org/10.1172/jci197345

BibTeX

@article{hernandez2026catecholamine,
author = {Hernandez, Nathaniel P and Chen, Jiegen and Qian, Yiling and Zhang, Xin and Wang, Yaomin and Ciszek, Brittney P and Gao, Xianglong and Klein, Marguerita E and Pai, Yun-Ling and Karaky, Mohamad and Meloto, Carolina Beraldo and Montagna, Francesca and Kanke, Matt and Crewe, Clair and Diatchenko, Luda and Sethupathy, Praveen and Nackley, Andrea G},
title = {{Catecholamine-mediated release of miR-133a-3p from adipocytes regulates the onset of chronic primary pain}},
journal = {The Journal of clinical investigation},
year = {2026},
month = jul,
volume = {136},
number = {17},
pages = {e197345},
publisher = {American Society for Clinical Investigation},
issn = {0021-9738},
doi = {10.1172/jci197345},
url = {https://doi.org/10.1172/jci197345},
pmid = {42479461},
pmcid = {PMC13528929}
}

RIS

TY - JOUR
AU - Hernandez, Nathaniel P
AU - Chen, Jiegen
AU - Qian, Yiling
AU - Zhang, Xin
AU - Wang, Yaomin
AU - Ciszek, Brittney P
AU - Gao, Xianglong
AU - Klein, Marguerita E
AU - Pai, Yun-Ling
AU - Karaky, Mohamad
AU - Meloto, Carolina Beraldo
AU - Montagna, Francesca
AU - Kanke, Matt
AU - Crewe, Clair
AU - Diatchenko, Luda
AU - Sethupathy, Praveen
AU - Nackley, Andrea G
TI - Catecholamine-mediated release of miR-133a-3p from adipocytes regulates the onset of chronic primary pain
T2 - The Journal of clinical investigation
J2 - J Clin Invest
PY - 2026
DA - 2026/07/21
VL - 136
IS - 17
SP - e197345
SN - 0021-9738
PB - American Society for Clinical Investigation
DO - 10.1172/jci197345
UR - https://doi.org/10.1172/jci197345
LA - en
ER -

CSL-JSON

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