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Non-Coding RNA
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3 July 2025

Role of ncRNAs in the Development of Chronic Pain

1
Program of Immunology and Immunotherapy, CIMA-Universidad de Navarra, 31008 Pamplona, Spain
2
Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, 31008 Pamplona, Spain
3
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
Non-Coding RNA2025, 11(4), 51;https://doi.org/10.3390/ncrna11040051
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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.

1. Introduction

The International Association for the Study of Pain (IASP) describes pain as “an unpleasant sensory and emotional experience often associated with actual or potential tissue damage” [1,2]. This definition highlights the multifaceted nature of pain, encompassing physical and emotional dimensions, and frequently indicating health issues that necessitate medical intervention [3,4,5]. The process of pain perception is initiated by the activation of nociceptors, which are specialized sensory neurons placed in peripheral tissues, including the skin, muscles, and internal organs [6]. These sensory neurons detect harmful stimuli, including mechanical pressure, extreme temperatures, and chemical changes indicative of potential tissue damage [7]. Upon stimulation, nociceptors create electrical signals that travel along afferent nerve fibers to the central nervous system (CNS), where they are processed and interpreted as pain [8]. However, it is important to note that pain involves some pathways within both the peripheral nervous system (PNS) and the CNS, allowing for multiple levels of modulation [9].
The characteristics of pain differ depending on its duration and etiology [10]. Acute pain is commonly brief and has a protective function, indicating immediate tissue injury and inducing behavioral responses to prevent further damages [11]. Conversely, chronic pain persists beyond the usual healing period, usually for years, and can become a debilitating condition affecting both physical and psychological well-being [12]. Chronic pain may arise from conditions including osteoarthritis [13], lower back pain [14], fibromyalgia [15], and cancer [16]. Unlike acute pain, which has a well-defined cause [11], chronic pain can develop into a distinct pathological condition, sometimes in the absence of tissue damage [17].
Chronic pain is particularly prevalent in older adults, as aging is associated with an increased incidence of pain-related conditions, including osteoarthritis, neuropathy and degenerative diseases [18]. Several epidemiological studies in Europe estimate that 38% to 60% of people aged 65 years and older experience chronic pain [19,20]. With advancing age, cumulative health conditions often exacerbate chronic pain, further impairing overall health and quality of life [21]. Several factors contribute to the risk of developing chronic pain, including age, gender, lifestyle and socioeconomic status [12]. Older people are particularly vulnerable due to physiological changes such as reduced tissue elasticity, muscle mass and bone density, all of which increase pain sensitivity and risk of injuries [22]. Gender differences in pain prevalence have also been observed, with women more likely to have chronic pain conditions [23]. In addition, modifiable lifestyle factors including smoking, alcohol consumption, obesity, and sedentary behavior can increase the likelihood of developing or worsening chronic pain [24,25,26].
These factors can influence gene expression and the regulation of pain-related pathways. In recent years, research has increasingly focused on the role of epigenetics in the modulation of chronic pain. Epigenetic modifications, such as DNA methylation [27], histone modifications [28] and non-coding RNAs (ncRNAs) [29], can modify gene expression without altering the underlying DNA sequence. ncRNAs have attracted considerable attention as regulators in the complex mechanisms underlying pain pathways. These molecules play a key role in regulating many biological processes essential for pain perception and response [30]. Unlike traditional protein-coding genes that directly encode proteins, ncRNAs exert their effects through regulatory functions that influence the expression of genes involved in some processes such as inflammation, neuronal plasticity and pain sensitivity [31,32,33].
Specifically, ncRNAs regulate gene expression by interacting with mRNA, chromatin, and other regulatory molecules, thereby influencing the activity of those genes implicated in pain pathways [34]. In the context of inflammation, ncRNAs can either promote or suppress the expression of pro-inflammatory cytokines and other signaling molecules, thus modulating the inflammatory response, which is a crucial contributor to pain [31,35]. Furthermore, it has been demonstrated that ncRNAs play a pivotal role in neuronal plasticity, a key factor in the development of chronic pain [32,36]. By modulating those genes that regulate synaptic strength, receptor sensitivity, and the formation of new neural connections, ncRNAs influence the persistence and exacerbation of pain following injury [37].
In conclusion, this article emphasizes the significant role of ncRNAs in the complex mechanisms that contribute to the onset and development of chronic pain. The following sections will explore the various types of ncRNAs and their roles in pain signaling, neural plasticity, and the regulation of pain-associated genes. A deeper understanding of the molecular interactions and regulatory functions of ncRNAs provides important insights into potential therapeutic approaches for chronic pain.

2. MicroRNAs (miRNAs)

MicroRNAs (miRNAs) constitute a subtype of small ncRNA molecules, usually ranging from 21 to 25 nucleotides in length, that act as key regulators of gene expression at the post-transcriptional level across a wide range of organisms, including plants, animals, and viruses [38,39,40]. These ncRNAs regulate gene expression by binding to complementary mRNA sequences, resulting in translational repression or mRNA degradation, ensuring precise and adaptable control of gene activity [41].
The biogenesis of miRNAs (Figure 1) is a multistep process that starts in the cell nucleus, where they are transcribed as primary miRNAs (pri-miRNAs) by RNA polymerase II, or in some cases, RNA polymerase III [42,43]. pri-miRNAs are further recognized and processed by the Drosha–DGCR8 microprocessor complex, which cleaves them into precursor miRNAs (pre-miRNAs) that are transported to the cytoplasm via exportin-5 (XPO5) in a RanGTP-dependent manner [44,45]. In the cytoplasm, pre-miRNAs are further cleaved by the endoribonuclease Dicer, resulting in the formation of mature miRNA duplexes [46]. From miRNA duplexes, only one strand (guide strand) is selectively incorporated into the RNA-induced silencing complex (RISC), while the passenger strand is commonly degraded [47]. Once integrated into the RISC, the miRNA directs the complex to specific mRNAs based on sequence complementarity, with binding primarily occurring in the 3′ untranslated region (3′ UTR) of the target gene [48], leading to either mRNA cleavage and degradation [49] or translation repression [50].
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].
This regulatory mechanism allows miRNAs to modulate gene networks with exceptional specificity and versatility, impacting a wide array of biological processes, including cell proliferation and differentiation [52], apoptosis [53], stress response [54], and immune function [55]. Furthermore, miRNAs are essential in intercellular communication by being released into extracellular fluids like blood, saliva, and urine. They are either encapsulated within exosomes and microvesicles [56,57,58] or associated with RNA-binding proteins such as argonaute (AGO), thereby functioning as systemic signaling molecules [59]. Given their crucial role in maintaining cellular homeostasis, disruptions in miRNA function are associated with numerous diseases, such as cancer [60], neurodegenerative disorders [61], cardiovascular diseases [62], and autoimmune conditions [63], positioning them as promising candidates for therapeutic intervention and biomarker discovery [64].
Advancements in bioinformatics and high-throughput sequencing technologies, like microarrays [65], RNA sequencing [66], and cross-linking immunoprecipitation (CLIP) assays [67], have enabled the identification of miRNA targets and expression patterns under several biological conditions, providing a more profound understanding of their biological functions [68]. As research continues to elucidate the complexities of miRNA networks, it has become increasingly clear that these small molecules exert remarkable control over gene expression, functioning as master regulators with significant implications for precision medicine, regenerative therapies, and disease intervention strategies [69].
Numerous studies have shown that certain miRNAs are upregulated in response to inflammatory mediators, playing a role in the enhancement of pain signaling by regulating the expression of cytokines, receptors, and ion channels involved in pain transmission [70,71]. In contrast, other miRNAs have been shown to attenuate excessive pain responses and promote various analgesic pathways [72,73]. Furthermore, miRNAs are implicated in the modulation of synaptic plasticity, a key process in the transition from acute to chronic pain, by influencing the expression of biomolecules linked to long-term potentiation (LTP) and long-term depression (LTD) in pain-processing areas including the spinal cord and brain [74]. Finally, recent studies have highlighted the potential of miRNAs as diagnostic biomarkers for chronic pain, as their expression profiles reflect the underlying pathological changes in pain pathways [75].
Table 1 outlines the altered expression of miRNAs in various preclinical chronic pain conditions, including inflammatory, neuropathic, and cancer-related pain. These miRNAs could serve as potential biomarkers or therapeutic targets.
Table 1. List of dysregulated miRNAs across chronic pain disorders. Abbreviations: SNL (spinal nerve ligation), CCI (chronic constriction injury), CIPN (chemotherapy-induced neuropathic pain), CFA (complete Freund’s adjuvant), SNI (spared nerve injury), CIVP (chronic inflammatory visceral pain), DPN (diabetic peripheral neuropathy), SCI (spinal cord injury), BCP (bone cancer pain), CRC (colorectal cancer), bCCI (bilateral chronic constriction injury), CCI-IoN (chronic constriction injury of the infraorbital nerve), CCD (chronic compression of the DRG), L5-VRT (L5 ventral root transection), AIA (adjuvant-induced arthritis), and BTZ (bortezomib).

3. Small Interfering RNAs (siRNAs)

Small interfering RNAs (siRNAs) are fundamental elements of the RNA interference (RNAi) pathway, a highly conserved regulatory mechanism that facilitates post-transcriptional gene silencing [149]. The biosynthesis of siRNAs, characterized as double-stranded RNA (dsRNA) molecules, initiates in the cytoplasm with the cleavage of endogenous or exogenous dsRNA substrates by the enzyme Dicer (Figure 2) [150]. Dicer, in combination with some cofactors (such as TRBP) in mammals, recognizes and cleaves the dsRNA into siRNA duplexes with characteristic two-nucleotide 3′ overhangs [151]. Subsequently, the siRNA duplexes are loaded into the RISC, where they undergo strand selection, a process mediated by the helicase activity of AGO proteins [152].
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].
The strand with the thermodynamically less stable 5′ end is preferentially retained as the guide strand, while the passenger strand is degraded [154,155]. The guide strand, incorporated into the mature RISC, facilitates sequence-specific gene silencing by recognizing and binding to complementary target mRNAs [155]. This binding enables the AGO-mediated endonucleolytic cleavage of the target transcript, leading to its degradation and preventing translation [156]. In certain organisms, amplification of the RNAi response occurs through RNA-dependent RNA polymerases (RdRPs), which generate secondary siRNAs from cleaved target mRNAs, thereby enhancing gene silencing [157,158].
A key feature of siRNAs is their antiviral function, where they specifically recognize and degrade viral RNA, thereby preventing viral replication [159]. Their ability to disrupt viral genomic material limits the progression of infection and enhances the host’s capacity to initiate an immune response [160]. In addition to their antiviral properties, siRNAs are crucial for maintaining genomic stability. siRNAs are crucial in silencing transposable elements, which are mobile genetic components capable of moving within the genome, potentially causing mutations and genomic instability [161], or contributing to the development of diseases such as cancer [149], neurodegenerative disorders [162], and genetic syndromes [163]. Conversely, siRNAs are involved in modulating gene expression, influencing the activation or repression of specific genes in response to various internal and external stimuli [164]. This function extends to cellular differentiation, where siRNAs contribute to the determination of cell fate during development, ensuring the proper identity and function of cells within tissues [165]. Moreover, siRNAs mediate many cellular responses to environmental stressors, including alterations in temperature, nutrient availability, and exposure to toxins [164].
Recent studies have highlighted the potential of siRNAs in pain management by selectively modulating the expression of genes involved in pain pathways. Through the targeted silencing of key molecules such as inflammatory cytokines [166], ion channels [167], and neurotransmitters [168], siRNAs offer a promising approach to developing effective and personalized therapies for chronic pain. Table 2 provides an overview of the siRNAs used for treating inflammatory, neuropathic, and cancer-related pain.
Table 2. List of siRNAs employed in the treatment of several chronic pain disorders. Abbreviations: CCI (chronic constriction injury), ERK (extracellular signal-regulated kinase), STAT3 (signal transducer and activator of transcription 3), CFA (complete Freund’s adjuvant), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), IL-1β (interleukin 1 beta), DPN (diabetic peripheral neuropathy), PARP1 (poly-ADP-ribose- polymerase 1), CIPN (chemotherapy-induced neuropathic pain), SNL (spinal nerve ligation), BCP (bone cancer pain), PDN (painful diabetic neuropathy), TLR4 (Toll-like receptor 4), PANX1 (pannexin 1), NLRP3 (NOD-like receptor family pyrin domain containing 3), SDH (spinal dorsal horn), IBA-1 (ionized calcium binding adapter molecule 1), PKC (protein kinase C), PI3K (phosphoinositide 3-kinase), PKB (protein kinase B), AAV (adeno-associated virus), SCI (spinal cord injury), LPS (lipopolysaccharide), CCL2 (C-C motif chemokine ligand 2), KCC2 (potassium chloride cotransporter 2), CACNA1H (calcium voltage-gated channel subunit alpha1 H), p-ERK (phosphorylated extracellular signal-regulated kinase), GFAP (glial fibrillary acidic protein), and OX42 (OX42 antigen/CD11b).

4. Long Non-Coding RNAs (lncRNAs)

Long non-coding RNAs (lncRNAs) represent a complex class of non-protein-coding transcripts that exceed 200 nucleotides in length [201]. lncRNAs have emerged as key regulators of gene expression at multiple levels, including chromatin remodeling [202], transcriptional and post-transcriptional modulation [203,204] across many organisms. Unlike miRNAs and siRNAs, which mainly function through base-pairing interactions with target mRNAs [41,154], lncRNAs regulate gene expression via a broad spectrum of mechanisms, acting as molecular scaffolds, decoys, sponges, and guides [205]. By facilitating the recruitment of specific protein complexes to genomic loci, they regulate gene expression in a context-dependent manner. However, developments in technology have shown that numerous lncRNAs contain small open reading frames (sORFs) capable of encoding micropeptides. These micropeptides mediate key biological functions, including the regulation of homeostasis, inflammation, immune responses, metabolism, and tumor progression [206].
The biogenesis of lncRNAs (Figure 3) shares similarities with that of protein-coding mRNAs. They are transcribed by RNA polymerase II and undergo several post-transcriptional modifications, including the addition of a 5′ cap, polyadenylation at the 3′ end, and splicing [207]. Despite these similarities, lncRNAs lack protein-coding potential due to the absence of long open reading frames (ORFs) and ribosomal translation initiation signals [208]. While some lncRNAs are polyadenylated, others remain non-polyadenylated, adding another layer of complexity to their function [209,210]. The expression of lncRNAs is often highly cell-type-specific and tightly regulated, with distinct spatial localization patterns that contribute to their functional diversity [211].
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.
Depending on their localization, lncRNAs can exert their effects either within the nucleus or the cytoplasm. Nuclear lncRNAs play crucial roles in chromatin architecture and epigenetic modifications, often interacting with chromatin-modifying complexes such as Polycomb Repressive Complex 2 (PRC2) to induce gene silencing through histone modifications [212,213]. Furthermore, lncRNAs can recruit transcription factors to specific genomic loci, regulating transcription in a gene-specific fashion [214]. Conversely, in the cytoplasm, lncRNAs affect mRNA stability, translation, and post-transcriptional regulation by interacting with RNA-binding proteins, miRNAs, and ribosomes [215]. One intriguing mechanism is their ability to function as competing endogenous RNAs (ceRNAs), wherein lncRNAs act as molecular sponges for miRNAs, thereby preventing miRNA-mediated repression of target genes [216]. This ceRNA network adds another regulatory layer to gene expression and has significant implications in various biological processes [217].
Functionally, lncRNAs are deeply embedded in numerous physiological processes, including cell differentiation [218], proliferation [219], apoptosis [220], immune responses [221], and genomic imprinting [222]. Furthermore, recent evidence indicates that lncRNAs can be involved in intercellular communication by being selectively incorporated into extracellular vesicles, such as exosomes [223]. Once secreted, these lncRNA-containing vesicles can be taken up by recipient cells, where they influence gene expression and cellular behavior, further highlighting their role in systemic regulation [223].
Given their regulatory roles, dysregulation of lncRNAs has been strongly associated with various diseases, including cancer [224], neurodegenerative disorders [225], cardiovascular diseases [226], and metabolic syndromes [227]. In cancer, dysregulated lncRNA expression can play a role in tumor initiation, progression, metastasis, and resistance to therapy by modulating oncogenic and tumor-suppressor pathways [224]. Some lncRNAs function as oncogenes, promoting tumor growth and invasion, while others act as tumor suppressors, inhibiting malignancy [228]. In neurodegenerative disorders, lncRNAs have been implicated in neuroinflammation, synaptic dysfunction, and protein aggregation, suggesting their potential as therapeutic targets [225]. On the other hand, in cardiovascular diseases, lncRNAs participate in cardiac hypertrophy and atherosclerosis, further emphasizing their broad biological significance [226]. Techniques such as RNA sequencing (RNA-seq) [229], chromatin isolation by RNA purification (ChIRP) [230], and CLIP [231] have provided valuable insights into lncRNA functions and their molecular interactions. These methodologies have provided a substantial toolkit for dissecting the complex regulatory networks mediated by lncRNAs. By mapping the interactions between lncRNAs and the DNA-RNA-protein complex, researchers can construct molecular interaction networks that reveal the roles of lncRNAs in gene regulation.
In the field of chronic pain research, increasing evidence suggests that lncRNAs play a significant role in modulating pain by regulating the expression of pro-nociceptive and anti-nociceptive genes, influencing neuroinflammatory pathways, and affecting synaptic plasticity in critical pain-processing regions such as the spinal cord and brain [232]. Some lncRNAs have been shown to contribute to pain sensitization through interactions with inflammatory cytokines, ion channels, and intracellular signaling pathways involved in pain transmission [233].
Finally, lncRNAs have emerged as valuable diagnostic biomarkers for chronic pain conditions, as their expression patterns reflect underlying pathological changes in pain-processing circuits. The detection of several lncRNAs in biofluids including blood [234], cerebrospinal fluid [235], and saliva [236] makes them promising candidates for non-invasive pain diagnostics. Identifying distinct lncRNA signatures associated with various pain conditions could support the development of precision medicine approaches, enabling personalized therapies tailored to individual patients [237]. Table 3 summarizes the alterations in the expression of lncRNAs observed across various preclinical models of chronic pain, including those related to inflammation, nerve injury, and cancer. These changes in lncRNA expression are significant as they could serve as biomarkers for the diagnosis of chronic pain conditions or as targets for the development of novel therapeutic approaches aimed at pain relief. Targeting these lncRNAs could facilitate the development of effective treatments for individuals afflicted with different types of chronic pain.
Table 3. List of dysregulated lncRNAs across chronic pain disorders. Abbreviations: CFA (complete Freund’s adjuvant), lncRNA (long non-coding RNA), MEG3 (maternally expressed gene 3), TRPV1 (transient receptor potential vanilloid 1), SNL (spinal nerve ligation), DRG (dorsal root ganglion), NEAT1 (nuclear enriched abundant transcript 1), mRNA (messenger RNA), TNFAIP1 (tumor necrosis factor alpha induced protein 1), AKT (protein kinase B), CREB (cAMP response element binding protein), BCP (bone cancer pain), siRNA (small interfering RNA), miRNA (microRNA), CXCL13 (C-X-C motif chemokine ligand 13), SCI (spinal cord injury), CXCR5 (C-X-C chemokine receptor type 5), CCI (chronic constriction injury), WNT5A (Wnt family member 5A), JMJD1A (Jumonji domain containing 1A), bCCI (bilateral chronic constriction injury), SOCS3 (suppressor of cytokine signaling 3), JAK2 (Janus kinase 2), STAT3 (signal transducer and activator of transcription 3), SNL (spinal nerve ligation), SNHG1 (small nucleolar RNA host gene 1), pSNL (partial spinal nerve ligation), BAI1 (brain-specific angiogenesis inhibitor 1), EZH2 (enhancer of zeste homolog 2), CXCL9 (C-X-C motif chemokine ligand 9), and c-Fos (FBJ murine osteosarcoma viral oncogene homolog).

5. Circular RNAs (circRNAs)

Circular RNAs (circRNAs) have attracted significant attention owing to their distinctive and remarkable structural characteristics, which differentiate them from conventional linear RNAs. Unlike linear RNAs that possess a 5′ cap and a 3′ poly(A) tail [252], circRNAs are distinguished by their covalently closed loop structures, which render them more stable and resistant to exonuclease-mediated degradation [253]. This stability contributes to the prolonged presence of circRNAs in various bodily fluids, positioning them in a wide range of physiological and pathological processes [254].
CircRNAs arise from pre-mRNAs via a non-canonical splicing mechanism known as back-splicing (Figure 4). In this process, a downstream splice donor site is connected to an upstream splice acceptor site, leading to the formation of a circRNA [255]. This back-splicing event contrasts with the typical linear splicing processes involved in the production of conventional mRNA molecules [256]. The different structural forms of circRNAs, including exonic circRNAs (ecircRNAs), circular intronic RNAs (ciRNAs), and exon-intron circRNAs (EIciRNAs), further support their roles in gene expression regulation and cellular functions [257,258,259]. The biogenesis of circRNAs is regulated by a host of factors, such as RNA-binding proteins (RBPs), spliceosome components, and cis-regulatory elements [260,261]. These factors help facilitate the back-splicing process, ensuring that circRNAs are produced in a controlled and context-specific manner. Key RBPs like MBL (mannose-binding lectin) and FUS (fused in sarcoma) are crucial for stabilizing circRNA formation by either aiding intronic base-pairing or recruiting the splicing machinery [262,263]. Furthermore, the complementary sequences within intronic regions play a critical role in determining the type and diversity of circRNAs that are expressed across different tissues and developmental stages [264].
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).
CircRNAs have been identified as important regulators of gene expression, particularly through their interactions with different miRNAs. One of the most documented roles of circRNAs is their capacity to function as molecular sponges for miRNAs [265]. By sequestering miRNAs, circRNAs prevent them from interacting with their target mRNAs, thereby modulating gene expression at the post-transcriptional level [266]. In addition to acting as miRNA sponges, circRNAs have also been implicated in modulating transcription, adjusting alternative splicing events, and even regulating translation [267,268,269]. Certain circRNAs have been shown to harbor internal ribosome entry sites (IRESs) or post-transcriptional modifications, such as N6-methyladenosine (m6A), which enable them to serve as templates for translation into functional peptides [270,271]. These functions underscore the versatility of circRNAs in cellular regulation and their potential involvement in many cellular processes, from proliferation to apoptosis [272]. The dysregulation of circRNAs has been implicated in a diverse array of pathological conditions, including cancer [273], neurodegenerative diseases [274], and cardiovascular disorders [275].
The role of circRNAs in sensory processing represents an energizing area of research, with emerging evidence suggesting that these ncRNAs may contribute significantly to the pathophysiology of pain. Within the context of chronic pain, specific circRNAs have been shown to be upregulated in pain-associated tissues, including the DRG (dorsal root ganglion) and spinal cord [276,277]. These circRNAs interact with miRNAs, thereby influencing the expression of genes that regulate pain signaling pathways. For instance, circRNAs regulate the expression of ion channels, like ASICs (acid-sensing ion channels), that are essential for the transmission of pain signals [278]. Moreover, several circRNAs have been shown to modulate the activity of pain-related transcription factors, such as AP-1 (activator protein 1) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), as well as signaling molecules including cytokines and neurotrophins, which are pivotal in the sensitization of nociceptors [279,280,281,282]. Through their ability to influence the expression of those genes involved in inflammation, neuronal excitability, and synaptic plasticity, circRNAs contribute to the complex network that regulates many chronic pain responses [283,284,285]. Especially, circRNAs that modulate numerous inflammatory responses have been shown to influence the onset and persistence of inflammatory pain. The dysregulation of circRNAs may contribute to the maintenance of chronic pain states by altering the balance between pro-inflammatory and anti-inflammatory signaling [286].
Finally, given their role in regulating gene expression and several cellular processes, circRNAs hold immense potential as both diagnostic biomarkers and therapeutic targets for diseases associated with chronic pain [287]. The implications of circRNAs in pain represent a promising frontier in both basic research and clinical applications. By understanding how circRNAs contribute to pain modulation and chronic pain conditions, researchers may develop novel therapeutic strategies aimed at alleviating pain through the manipulation of circRNA function [288,289]. In this way, circRNAs may emerge as key players in the next generation of pain management therapies, potentially offering new hope for patients suffering from chronic pain disorders.
Table 4 presents a comprehensive overview of circRNA expression alterations identified in various preclinical models of chronic pain, including those linked to inflammation, neuropathies, and cancer. These alterations are highly relevant, as they could be used as biomarkers for the diagnosis of chronic pain or as targets for the development of novel therapeutic approaches in pain management.
Table 4. List of dysregulated circRNAs in chronic pain conditions. Abbreviations: CIVP (chronic inflammatory visceral pain), GFAP (glial fibrillary acidic protein), CFA (complete Freund’s adjuvant), DPN (diabetic peripheral neuropathy), DRG (dorsal root ganglion), STZ (streptozotocin), CCI (chronic constriction injury), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), IL-1β (interleukin 1 beta), IL-6 (interleukin 6), TNF-α (tumor necrosis factor alpha), SLICK (sequence like an intermediate conductance K channel), ENO1 (enolase 1), DHX9 (DEAH-box helicase 9), UBR5 (ubiquitin protein ligase E3 component N-recognin 5), ALB (albumin), COX-2 (cyclooxygenase 2), IL-10 (interleukin 10), CCI-IoN (chronic constriction injury of the infraorbital nerve), IST1 (increased sodium tolerance 1), LC3-II (microtubule-associated protein 1 light chain 3-II), p62 (Sequestosome 1-SQSTM1-), 3′-UTR (3′-untranslated region), KCNK1 (potassium channel, two-pore domain subfamily K, member 1), SNI (spared nerve injury), GAD65 (glutamate decarboxylase 65), NK1R (neurokinin 1 receptor), SNL (spinal nerve ligation), VEGFB (vascular endothelial growth factor B), Ybx1 (Y-Box binding protein 1), Wnt5a (Wnt family member 5A), LPAR3 (lysophosphatidic acid receptor 3), and BCP (bone cancer pain).

6. Conclusions

The role of ncRNAs in the development of chronic pain is increasingly recognized as a key area of research with significant therapeutic potential (Table 5). ncRNAs, including miRNAs, siRNAs, lncRNAs, and circRNAs, have emerged as pivotal regulators of gene expression, impacting numerous cellular processes linked to pain perception and chronic pain pathophysiology. These biomolecules regulate the expression of pain-related genes, influence neuroinflammation, alter ion channel function, and affect the plasticity of neural circuits involved in pain processing. Dysregulation of ncRNA has been associated with some chronic pain conditions, underscoring their role as potential biomarkers for diagnosis and targets for treatment.
Table 5. Comparative overview of ncRNA types involved in chronic pain: stability, specificity, and translational challenges. Abbreviations: ncRNA (non-coding RNA), miRNA (microRNA), siRNA (small interfering RNA), circRNA (circular RNA), and lncRNA (long non-coding RNA).
A growing body of evidence supports the differential expression of numerous classes of ncRNAs in both animal models and human patients with chronic pain conditions, including neuropathic, inflammatory, and cancer-related pain. These results emphasize the prospective utility of ncRNAs as minimally invasive diagnostic biomarkers, detectable in biofluids including blood and cerebrospinal fluid, offering new promising possibilities for early detection, pain subtyping, and monitoring of treatment responses [307]. Additionally, recent research highlights that miRNAs function as suppressors of mRNA translation, leading to reduced protein levels of pain modulators, while lncRNAs and circRNAs act as molecular sponges, sequestering miRNAs and influencing their regulatory activities. siRNAs also play a crucial role in this regulatory network by promoting the degradation of specific mRNA. The complex interactions between these ncRNAs and their target molecules suggest a sophisticated regulatory network that contributes to both the persistence and intensification of chronic pain states. Understanding these complex interactions opens new avenues for the development of ncRNA-based therapeutics, such as miRNA mimics [308], antagomirs [309], lncRNA modulators [310], and siRNA-based treatments [311], aiming to restore normal gene expression patterns and alleviate pain.
However, despite these advances, significant barriers hinder the clinical translation of ncRNA-based diagnostics and therapeutics. These include challenges related to the stability, specificity, and immunogenicity of RNA-targeting agents, efficient delivery across biological barriers (particularly the blood–brain barrier), and the risk of off-target effects due to the pleiotropic and context-dependent nature of ncRNA function [312]. Interindividual variability in ncRNA expression profiles, differences across pain etiologies, and the current lack of standardized detection and quantification methods further complicate clinical implementation [313]. To overcome these limitations, future research should prioritize the development of targeted delivery systems (e.g., nanoparticle-based platforms), refine computational tools for predicting ncRNA-target interactions, and conduct clinical studies to validate candidate ncRNAs across diverse patient populations [314,315,316]. In parallel, regulatory frameworks must adapt to the unique characteristics of RNA-based therapeutics. Through the resolution of these challenges, the field can advance toward the clinical integration of ncRNA-based strategies, ultimately contributing to more precise, personalized, and effective approaches to chronic pain management.
In conclusion, ncRNAs show significant potential for elucidating the complex mechanisms underlying chronic pain and developing innovative strategies. Continued exploration of ncRNA biology will be essential to overcoming current limitations and harnessing their full therapeutic potential in the management of chronic pain.

Funding

This research received no external funding.

Data Availability Statement

Not applicable. No new data were generated.

Acknowledgments

I gratefully acknowledge BioRender for providing a professional and scientifically rigorous platform that enabled the creation of high-quality graphical illustrations presented in this review.

Conflicts of Interest

The author declares no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
3′-UTR3′-untranslated region
AAVAdeno-associated virus
AGOArgonaute
AGO2Argonaute 2
AIAAdjuvant-induced arthritis
AKTProtein kinase B
ALBAlbumin
AP-1Activator protein 1
ASICAcid-sensing ion channel
BAI1Brain-specific angiogenesis inhibitor 1
bCCIBilateral chronic constriction injury
BCPBone cancer pain
BTZBortezomib
CACNA1HCalcium voltage-gated channel subunit alpha1 H
CCDChronic compression of the DRG
CCIChronic constriction injury
CCI-IoNChronic constriction injury of the infraorbital nerve
CCL2C-C motif chemokine ligand 2
ceRNACompeting endogenous RNA
CFAComplete Freund’s adjuvant
c-FosFBJ murine osteosarcoma viral oncogene homolog
ChIRPChromatin isolation by RNA purification
ciRNACircular intronic RNA
circRNACircular RNA
CIPNChemotherapy-induced neuropathic pain
CIVPChronic inflammatory visceral pain
CLIPClass II-associated invariant chain peptide
CNSCentral nervous system
COX-2Cyclooxygenase 2
CRCColorectal cancer
CREBcAMP response element binding protein
CXCL13C-X-C motif chemokine ligand 13
CXCL9C-X-C motif chemokine ligand 9
CXCR5C-X-C chemokine receptor type 5
DGCR8DiGeorge Syndrome critical region 8
DNADeoxyribonucleic acid
DPNDiabetic peripheral neuropathy
DRGDorsal root ganglion
DHX9DEAH-box helicase 9
dsRNADouble-strand RNA
ecircRNAExonic circRNA
EIciRNAExon-intron circRNA
ENO1Enolase 1
ERKExtracellular signal-regulated kinase
EZH2Enhancer of zeste homolog 2
FUSFused in sarcoma
GAD65Glutamate decarboxylase 65
GFAPGlial fibrillary acidic protein
GTPGuanosine triphosphate
IASPInternational Association for the Study of Pain
IBA-1Ionized calcium binding adapter molecule 1
IFT52Intraflagellar transport 52
IFT88Intraflagellar transport 88
IKBKBInhibitor of NF-κB
IL-1βInterleukin 1 beta
IL-10Interleukin 10
IL-6Interleukin 6
IRESInternal ribosome entry site
IST1Increased sodium tolerance 1
JAK2Janus kinase 2
JMJD1AJumonji domain containing 1A
KCC2Potassium chloride cotransporter 2
KCNK1Potassium channel, two-pore domain subfamily K, member 1
L5-VRTL5 ventral root transection
lncRNALong non-coding RNA
LC3-IIMicrotubule-associated protein 1 light chain 3-II
LPAR3Lysophosphatidic acid receptor 3
LPSLipopolysaccharide
LTDLong-term depression
LTPLong-term potentiation
m6AN6-methyladenosine
MBLMannose-binding lectin
MEG3Maternally expressed gene 3
miRNAMicroRNA
mRNAMessenger RNA
NAMPTNicotinamide phosphoribosyltransferase
ncRNANon-coding RNA
NEAT1Nuclear enriched abundant transcript 1
NF-κBNuclear factor kappa-light-chain-enhancer of activated B cells
NK1RNeurokinin 1 receptor
NLRP3NOD-like receptor family pyrin domain containing 3
NR2BN-methyl-D-aspartate receptor subunit 2B
ORFOpen reading frame
OX42OX42 antigen/CD11b
p62Sequestosome 1 (SQSTM1)
PANX1Pannexin 1
PARP1Poly(ADP-ribose) polymerase 1
p-ERKPhosphorylated extracellular signal-regulated kinase
PDNPainful diabetic neuropathy
PI3KPhosphoinositide 3-kinase
PI3KCBPhosphoinositide 3-kinase catalytic subunit beta
PKBProtein kinase B
PKCProtein kinase C
PKM2Pyruvate kinase M2
PNSPeripheral nervous system
PRC2Polycomb repressive complex 2
pre-mRNAPrecursor messenger RNA
pre-miRNAPrecursor microRNA
pri-miRNAPrimary microRNA
pSNLPartial spinal nerve ligation
PVT1Plasmacytoma variant translocation 1
RanRas-related nuclear protein
RBPRNA-binding protein
RdRPsRNA-dependent RNA polymerase
RISCRNA-induced silencing complex
RNARibonucleic acid
RNA Pol IIRNA polymerase II
RNA Pol IIIRNA polymerase III
RNA-seqRNA sequencing
SCISpinal cord injury
SDHSpinal dorsal horn
SGK3Serum/glucocorticoid regulated kinase family member 3
siRNASmall interfering RNA
SLICKSequence like an intermediate conductance K channel
SNHG1Small nucleolar RNA host gene 1
SNISpared nerve injury
SNLSpinal nerve ligation
SOCS3Suppressor of cytokine signaling 3
STAT3Signal transducer and activator of transcription 3
STZStreptozotocin
TET1Ten-eleven translocation methylcytosine dioxygenase 1
TLR4Toll-like receptor 4
TNFAIP1Tumor necrosis factor alpha induced protein 1
TNF-αTumor necrosis factor alpha
TRBPTransactivation response element RNA-binding protein
TRPV1Transient receptor potential vanilloid 1
U1-snNRPU1 small nuclear ribonucleoprotein
UBR5Ubiquitin protein ligase E3 component N-recognin 5
VEGFBVascular endothelial growth factor B
WNT5AWnt family member 5A
Ybx1Y-Box binding protein 1
XPO5Exportin 5

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Correction: Piergentili et al. miR-125 in Breast Cancer Etiopathogenesis: An Emerging Role as a Biomarker in Differential Diagnosis, Regenerative Medicine, and the Challenges of Personalized Medicine. Non-Coding RNA 2024, 10, 16
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