Abstract
Chronic inflammatory pain seriously affects patients' quality of life because of a paucity of effective clinical treatments caused, at least in part, by lack of full understanding of the underlying mechanisms. miRNAs are known to be involved in inflammatory pain via silencing or degrading of target mRNA in the cytoplasm. The present study provides a novel mechanism by which miRNA-22 positively regulates metal-regulatory transcription factor 1 (Mtf1) in the nuclei of neurons in the dorsal horn of the spinal cord. We found that miRNA-22 was significantly increased in the dorsal horn of mice with either inflammatory pain induced by plantar injection of complete Freund's adjuvant (CFA) or neuropathic pain induced by unilateral sciatic nerve chronic constrictive injury (CCI). Knocking down or blocking miRNA-22 alleviated CFA-induced mechanical allodynia and heat hyperalgesia, whereas overexpressing miRNA-22 produced pain-like behaviors. Mechanistically, the increased miRNA-22 binds directly to the Mtf1 promoter to recruit RNA polymerase II and elevate Mtf1 expression. The increased Mtf1 subsequently enhances spinal central sensitization, as evidenced by increased expression of p-ERK1/2, GFAP, and c-Fos in the dorsal horn. Our findings suggest that the miRNA-22–Mtf1 signaling axis in the dorsal horn plays a critical role in the induction and maintenance of inflammatory pain. This signaling pathway may be a promising therapeutic target in inflammatory pain.
Highlights
Epigenetic mechanisms play a critical role in the development and maintenance of chronic pain [1–5]. microRNAs, a class of non-coding RNAs 20–25 nucleotides in length, are highly conserved and stable, and recent studies have shown a strong connection between miRNAs and various diseases of the nervous system
The pathogenesis of chronic inflammatory pain involves peripheral and/or central sensitization and activation of glial cells: these changes are attributed to aberrant neurotransmitter release and activity in intracellular signaling pathways at various levels in the nervous system, including the dorsal root ganglia (DRG), spinal cord, and brain [23–27]
The dorsal horn of the spinal cord links the peripheral nervous system to the central nervous system and is is a critical component in the transmission of nociception information; as such, it is a key target in the development of analgesic therapeutics and diagnostic strategies for pain
Summary
Epigenetic mechanisms play a critical role in the development and maintenance of chronic pain [1–5]. microRNAs (miRNAs), a class of non-coding RNAs 20–25 nucleotides in length, are highly conserved and stable, and recent studies have shown a strong connection between miRNAs and various diseases of the nervous system. Epigenetic mechanisms play a critical role in the development and maintenance of chronic pain [1–5]. MiRNA-1224, located mainly in the nuclei of spinal neurons, is downregulated by peripheral inflammation; rescuing this downregulation attenuates inflammation-induced nociceptive hypersensitivity by reducing the level of ciRNA-Filip in the dorsal horn [5], suggesting that nuclear miRNAs can play an important role in the pathological processes underlying inflammatory pain. Given that miRNA-22 is highly conserved across mouse and human and participates in several diseases, including Alzheimer’s disease, glioma, and hepatocellular carcinoma [12–14], it is likely to be a player in the physiological and pathological processes of multiple peripheral and central nervous diseases. Upregulation of miRNA-22 in the dorsal horn was required for the development and maintenance of inflammatory pain through its positive regulation of Mtf protein. Nuclear miRNA-22 in dorsal horn neurons may play a critical role in the pathological processes underlying inflammatory pain
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