Catecholamine-mediated release of miR-133a-3p from adipocytes regulates the onset of chronic primary pain
Nathaniel P. Hernandez, Jiegen Chen, Yiling Qian, Xin Zhang, Yaomin Wang, Brittney P. Ciszek, Xianglong Gao, Marguerita E. Klein, Yun-Ling Pai, Mohamad Karaky, Carolina Beraldo Meloto, Francesca Montagna, Matt Kanke, Clair Crewe, Luda Diatchenko, Praveen Sethupathy, Andrea G. Nackley
Nathaniel P. Hernandez, Jiegen Chen, Yiling Qian, Xin Zhang, Yaomin Wang, Brittney P. Ciszek, Xianglong Gao, Marguerita E. Klein, Yun-Ling Pai, Mohamad Karaky, Carolina Beraldo Meloto, Francesca Montagna, Matt Kanke, Clair Crewe, Luda Diatchenko, Praveen Sethupathy, Andrea G. Nackley
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Research Article Endocrinology Neuroscience

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

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.

Authors

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

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Figure 6

Neuronal miR-133a-3p regulates the levels of pain-relevant mRNA targets in vivo.

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Neuronal miR-133a-3p regulates the levels of pain-relevant mRNA targets ...
(A) Representative confocal image of DAPI, NeuN, miR-133a-3p, and MAP3K3 in the spinal dorsal horn of male and female PFC and PPC mice. Supporting graphs show quantification of signal intensity and Pearson’s correlation, which demonstrated significant negative relationships between miR-133a-3p and MAP3K3. (B) Representative confocal image of DAPI, NeuN, miR-133a-3p, and NUMB in the spinal dorsal horn of male and female PFC and PPC mice, with similar quantifications and findings. (C) Representative confocal images of DAPI, IBA1, GFAP, and miR-133a-3p in the spinal dorsal horn. Quantification of miR-133a-3p colocalization with neurons (NeuN+), astrocytes (GFAP+), and microglia (IBA1+) by Mander’s coefficient. N = 3–5 mice/sex/group; each data point represents the average of 3 sections per mouse. Scale bars: 200 μm. Data are presented as the mean + SEM. Data were analyzed by ANOVA followed by Tukey’s HSD post hoc test. *P < 0.05.