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

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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.

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 B. Meloto, Francesca Montagna, Matt Kanke, Clair Crewe, Luda Diatchenko, Praveen Sethupathy, Andrea G. Nackley