Role of ncRNAs in the Development of Chronic Pain

Abstract

Chronic pain is a multifactorial and complex condition that significantly affects individuals' quality of life. The underlying mechanisms of chronic pain involve complex alterations in neural circuits, gene expression, and cellular signaling pathways. Recently, ncRNAs, such as miRNAs, lncRNAs, circRNAs, and siRNAs, have been identified as crucial regulators in the pathophysiology of chronic pain. These ncRNAs modulate gene expression at both the transcriptional and post-transcriptional levels, affecting pain-related pathways like inflammation, neuronal plasticity, and sensory processing. miRNAs have been shown to control genes involved in pain perception and nociceptive signaling, while lncRNAs interact with chromatin remodeling factors and transcription factors to modify pain-related gene expression. CircRNAs act as sponges for miRNAs, thereby influencing pain mechanisms. siRNAs, recognized for their gene-silencing capabilities, also participate in regulating the expression of pain-related genes. This review examines the diverse roles of ncRNAs in chronic pain, emphasizing their potential as biomarkers for pain assessment and as targets for novel therapeutic strategies. A profound understanding of the ncRNA-mediated regulatory networks involved in chronic pain could result in more effective and personalized pain management solutions.

Keywords: chronic pain; circRNA; lncRNA; miRNA; ncRNA; siRNA.

Figure 1

The biosynthesis of miRNAs begins in the nucleus with the transcription of miRNA genes, generating pri-miRNAs. These pri-miRNAs are then processed by the Drosha protein, which enzymatically cleaves them to generate pre-miRNAs. Subsequently, pre-miRNAs are exported to the cytoplasm via the XPO5 protein. Once in the cytoplasm, pre-miRNAs undergo further maturation through the coordinated action of TRBP, Dicer, AGO2, and the RISC protein. This final step yields mature miRNAs, which are responsible for targeting mRNAs. Abbreviations: RNA Pol II/III (RNA polymerases II and III), miRNA (microRNA), pri-miRNA (primary microRNA), pre-miRNA (precursor microRNA), XPO5 (exportin 5), TRBP (transactivation response element RNA-binding protein), AGO2 (argonaute 2), RISC (RNA-induced silencing complex), and mRNA (messenger RNA). Figure adapted from Ref. [51].

Figure 2

The biosynthesis of siRNAs begins with the formation of dsRNA, which is recognized and cleaved by the enzyme Dicer into small interfering siRNAs. One strand of the siRNA is then incorporated into the RISC, guiding it to a complementary mRNA. RISC binds to the target mRNA and cleaves it at a specific site, contributing to its degradation and preventing protein biosynthesis. Abbreviations: dsRNA (double-strand RNA), RISC (RNA-induced silencing complex), and mRNA (messenger RNA). Figure adapted from Ref. [153].

Figure 3

lncRNAs are mainly transcribed by RNA polymerase II from non-coding genomic regions. Their biosynthesis closely resembles mRNA processing, encompassing transcription initiation, elongation, splicing, 5′ capping, and 3′ polyadenylation. lncRNAs act as molecular sponges for miRNAs, inhibiting miRNA-mediated repression of target genes. Abbreviations: RNA pol II (RNA polymerase II), lncRNA (long non-coding RNA), miRNA (microRNA), and mRNA (messenger RNA). Figure created with BioRender 23.

Figure 4

circRNAs are generated via the back-splicing of precursor mRNAs, resulting in RNA molecules that are covalently closed. These circRNAs participate in the regulation of gene expression by functioning as molecular sponges for miRNAs. Through their interaction with miRNAs, circRNAs inhibit their ability to target mRNAs, thereby modulating gene expression. In a similar fashion, circRNAs can sequester RBPs, influencing several processes such as translation, protein recruitment, and RNA processing. Abbreviations: U1-snRNP (U1 small nuclear ribonucleoprotein), RNA pol II (RNA polymerase II), DNA (deoxyribonucleic acid), circRNA (circular RNA), pre-mRNA precursor messenger RNA), EIciRNA (exon-intron circRNA), ecircRNA (exonic circRNA), ciRNA (circular intronic RNA), miRNA (microRNA), RBP (RNA-binding protein), TET1 (ten-eleven translocation methylcytosine dioxygenase 1). Figure adapted from an original illustration created with BioRender 23 (Authorship: Martina Maritan).