Abstract
Neuropathic pain (NP) following a spinal cord injury (SCI) is often hard to control and therapies should be focused on the physical, psychological, behavioral, social, and environmental factors that may contribute to chronic sensory symptoms. Novel therapeutic treatments for NP management should be based on the combination of pharmacological and nonpharmacological options. Some of them are addressed in this review with a focus on mechanisms and novel treatments. Several reports demonstrated an aberrant expression of non-coding RNAs (ncRNAs) that may represent key regulatory factors with a crucial role in the pathophysiology of NP and as potential diagnostic biomarkers. This review analyses the latest evidence for cellular and molecular mechanisms associated with the role of circular RNAs (circRNAs) in the management of pain after SCI. Advantages in the use of circRNA are their stability (up to 48 h), and specificity as sponges of different miRNAs related to SCI and nerve injury. The present review discusses novel data about deregulated circRNAs (up or downregulated) that sponge miRNAs, and promote cellular and molecular interactions with mRNAs and proteins. This data support the concept that circRNAs could be considered as novel potential therapeutic targets for NP management especially after spinal cord injuries.
Introduction: origin and classification of pain after SCI
The estimated annual incidence for spinal cord injury (SCI) is 15–40 cases per million, mostly affecting young adults with severe and permanent disabilities (Berg et al. 2011; Johansson et al. 2021; Miyakoshi et al. 2021; Witiw and Fehlings 2015). The pathophysiology of SCI involves primary and secondary mechanisms that affect sensory, motor, and autonomic function below the level of injury (Witiw and Fehlings 2015). The primary injury includes physical and mechanical trauma, contusion, compression, and concussion, which cause local, segmental, and limited damage to the spinal cord, generating breakage or contusion of axons, hemorrhage, ischemia, and edema (Ahuja et al. 2017; Park et al. 2004; Witiw and Fehlings 2015). The later events after a primary injury involve a complex cascade of degenerative processes termed secondary injury. Temporally, the secondary damage considerably amplifies the destruction of neuronal and glial cells in areas adjacent to the primary injury (Brockie et al. 2021; Park et al. 2004) mainly by excitotoxicity process due to excessive release of glutamate. Pain is a consequence and frequent complication of SCI (Burke et al. 2017; Finnerup et al. 2001). After SCI, pain also referred to as “central pain” is related to emotional discomfort and limitation of physical activity, participation in work and social events, thus deteriorating the quality of life of the patient (Burke et al. 2017; Finnerup 2013; Hassanpour et al. 2012; Masri and Keller 2012). Central pain initiated by SCI manifests in diverse ways at any level of the spinal cord (Hunt et al. 2021; Wang et al. 2021c). The International Spinal Cord Injury Pain (ISCIP) designed a classification of pain directly related to SCI: nociceptive, neuropathic, other or unknown pain, which depend on the source and/or pathology (Bryce et al. 2012a, b). In particular, neuropathic pain (NP) often accompanies the functional deficits associated with SCI and is manifested with chronic sensory symptoms and signs (Burke et al. 2017). With this classification pain is defined as nociceptive (musculoskeletal or visceral), neuropathic (at-level or below-level of the spinal injury) or undefined pain (neither nociceptive nor neuropathic) (Latremoliere and Woolf 2009; Widerström-Noga 2017). Although there are distinct definitions of NP it is widely accepted that it is caused by a lesion or disease of the somatosensory system. Indeed, patients suffering from NP present spontaneous persistent pain and a variety of abnormally evoked responses to innocuous stimuli (allodynia) or increased response to noxious stimuli (hyperalgesia). Nowadays, SCI patients often develop NP that is refractory to treatment and is associated with adverse effects or withdrawal reactions that limit drug usefulness (Colloca et al. 2017). Thus, caution must be used when selecting treatment (Thomas et al. 2022). Indeed, clinical trials approved by the FDA are devised to reduce the toxicity and addictive potential of steroidal anti-inflammatory drugs employed for SCI (Mazaleuskaya et al. 2021).
Novel pharmacological interventions to treat NP after SCI
The most frequently used drugs include pregabalin, gabapentin, duloxetine (serotonin-noradrenaline reuptake inhibitor), various tricyclic antidepressants, capsaicin (the active component of chili peppers), lidocaine, and weak or strong opioids (tramadol) (Colloca et al. 2017; Wiffen et al. 2017). However, several clinical studies now point to the importance of achieving safe and efficacious treatment of pain by reducing the side effects of opioid prescription (Britch and Walsh 2022; Mazaleuskaya et al. 2021). Indeed, the use of natural compounds, such as glycosides (related to sugar metabolism) and resveratrol (stilbenoid polyphenol) obtained from medical plants have potential use for NP treatment (Miguel et al. 2021; Tian et al. 2021).
Antisense oligonucleotides are an increasingly represented class of drugs used to modulate expression levels by targeting both coding and non-coding RNA and are under FDA approval for genetic diseases, cancer, and neurodegenerative diseases (Quemener et al. 2022). On the other hand, immunomodulatory oligodeoxynucleotides (ODNs) are synthetic molecules that influence different types of cells of the vertebrate immune system. Indeed, IMT504, a prototype of the PyNTTTTGT family of ODNs (Coronel et al. 2008; Elias et al. 2003) has been shown to have promising translational results given its low toxicity and its beneficial effects on animal models of neuropathic pain and diabetes (Bianchi et al. 2012; Casadei et al. 2022; Coronel et al. 2008; Leiguarda et al. 2018, 2021a, 2021b). It has also been reported that the systematic application of IMT504 induces the mobilisation of mesenchymal stem cells to the peripheral blood, a phenomenon which could be involved in a modulation of the inflammatory response by molecular mechanisms that remain to be established (Zorzopulos et al. 2017). The regulation of the inflammatory response and its molecular mechanism could be a potential therapeutic strategy to improve prognosis and pain modulation after SCI. Unfortunately, NP after SCI is still difficult to treat, largely because the underlying mechanisms are not yet fully understood. Thus, with a better understanding of the molecular mechanisms, optimal approaches to manage NP can be achieved which in turn could be crucial to develop novel diagnostic and treatment tools.
Overview of molecular modulators during evolvement and progression of neuropathic pain
NP after SCI is complex and develops as a consequence of a cascade of molecular events that lead to plastic changes that contribute to the development and maintenance of pain and remain incompletely understood. The pathophysiology of NP principally affects sensory fibers (Aβ, Aδ and C fibers) and involves many signaling cascades (Colloca et al. 2017; Finnerup et al. 2001; Nikolenko et al. 2022), such as neuroinflammatory response to injury, ectopic action potential discharge, upregulation of chemokines and chemokine receptors (Knerlich-Lukoschus et al. 2011), changes in calcium channel expression (Boroujerdi et al. 2011; Park and Luo 2010), modulation of expression and function of N-Methyl-D-Aspartate (NMDA) (Qu et al. 2009) and purine receptors, or opioids metabolism (Burnstock 2020; Chen et al. 2012; Detloff et al. 2014; Wang et al. 2021b), and brain-derived neurotrophic factor (BDNF) (Geng et al. 2010; Qu et al. 2009). After SCI there is also an alteration in the gain of excitation and the modulation of the inhibition with a significant role for extrasynaptic GABAA receptors in sparing spinal cord neurons from injury (Mazzone and Nistri 2019; Mazzone et al. 2021). Indeed, the changes in sensory pathways towards hyperexcitability over time might contribute to the NP becoming chronic (Colloca et al. 2017; Finnerup et al. 2021). Similarly, several reports have analysed the basis of cellular targets and circuits for persistent pain conditions, that are initiated by dysregulation of primary sensory neurons in the spinal cord network and brain, to explain peripheral plasticity in pathological disease state (Kuner 2010; Prescott et al. 2014; von Hehn et al. 2012). Indeed, the communication between brain and periphery, which occurs bidirectionally through reciprocal autonomic nervous system mechanisms, hormones and humoral factors, is regulated by the cholinergic anti-inflammatory pathway (Pavlov and Tracey 2005) and it is an important regulatory point for inflammation-related pain diseases with numerous therapeutic potential currently under clinical trials (Kelly et al. 2022). In this line it was recently demonstrated in 49 female patients with fibromyalgia syndrome that 19 microRNA regulators of cholinergic transcripts, such as has-miR-27b-3p, has-miR-148a-3p, and has-miR-182-5p, are dysregulated in support of the theory that microRNA control immune cell processes (Erbacher et al. 2022).
On the other hand, emerging evidence has shown that the dorsal horn neurons of the spinal cord contribute to pain-like hypersensitivity through the transitory expression of VGLUT3 for mechanical allodynia (Peirs et al. 2015). The immune responses in the dorsal horn have been implicated in SCI-pain, but immune mechanisms in the periphery, especially in the dorsal root ganglia (DRG), where nociceptor cell bodies reside, have not been elucidated. Chronic pain (such as inflammatory and NP) is believed to be caused by aberrant neuronal responses along the pain transmission pathway from peripheral spinal cord, thalamus and cortex (Zhuo 2007). Besides that, sensory neuron-associated macrophages (sNAMs) have been involved in the pathophysiology of neuropathic pain via proinflammatory and pronociceptive mediators (Yu et al. 2020). The activation of sNAMs after a systemic injury has been suggested to stimulate the immune receptors Toll-like receptors (TLRs) (Lacagnina et al. 2018; Liu et al. 2012), which induce proinflammatory factors such as chemokines/cytokines (Yu et al. 2020). In addition, the cytoplasmic nucleotide-binding oligomerization domain-like receptors (NLRs), such as nucleotide-binding oligomerization domain 2 (NOD2) commonly expressed in the microglial cells, have been found to be upregulated in sNAMs of the sensory ganglia after peripheral nerve injury. The stimulation of NLRs may recruit receptor-interacting serine/threonine-protein kinase 2 (Santa-Cecília et al. 2019), which in turn activates the nuclear transcription factor kappa B regulating the transcription of proinflammatory genes (Hasegawa et al. 2008; Santa-Cecília et al. 2019), suggesting that TLRs and NLRs may play an important role in the development of NP.
Neurons and glial cells (astrocytes and microglia) have close interactions regulating the initiation and maintenance of NP (Crown 2012; Tsuda 2016), in fact, the time course of astrocyte activation has been shown to coincide with the transition from the acute to chronic states during NP (Donnelly et al. 2020; Li et al. 2019). In this context, it has been reported that chronic inflammation-induced hyperalgesia and NP are associated with reduced levels of serine–threonine kinase G-protein receptor kinase 2 (GRK 2) in spinal microglia/macrophage (Willemen et al. 2010). Recently, it has been reported in a mouse model of inflammatory pain that the neuronal spinal GRK2 mediates microglial activation and neuroinflammation (Chen et al. 2022b). Other factors, such as cell-surface receptors for neurotransmission, the mitogen-activated protein kinases, the extracellular signal-regulated protein kinase and c-Jun N-terminal kinase (MAPKs, ERK, and JNK), the proinflammatory cytokines and neurotrophic factors expression (Chen et al. 2022b; Crown 2012; Kobayashi et al. 2008; Willemen et al. 2010; Zhuang et al. 2005), have been also shown to promote NP through the activation of spinal microglia.
In this sense, studies based on electroacupuncture (EA) treatment have demonstrated that alleviation of spinal nerve ligation (SNL)-induced NP is promoted by inhibiting spinal microglial and astrocyte activation (Liang et al. 2016). The central mechanism of EA-induced analgesia has been partially attributed to the reduction of the expression of p-38 MAPK on microglia (Liang et al. 2016). Following this line, a recent study has reported that EA treatment alleviates NP by decreasing abnormal dendritic spine/synaptic reconstruction and inflammation via P2X7 receptor (P2X7R) downregulation during activation in microglia during the development of NP (Wu et al. 2021). In addition, the CXCL12/CXCR4 signaling pathway expression has also been found to be activated in chronic post-ischemia pain models. CXCL12 is mainly expressed in neurons and microglia while CXCR4 is both in neurons and astrocytes as important regulator and contributor to the development and maintenance of NP via peripheral and central sensitization mechanisms (Dubový et al. 2010; Liu et al. 2019; Luo et al. 2016; Shen et al. 2014). Interestingly, some investigations have also suggested that the regulation of pathological pain would differ between sexes (Chen et al. 2018), due to cellular and molecular signaling pathways induced by sex-hormones fluctuations in females. All these data support the concept that the inflammatory processes may contribute to develop and maintain NP induced by chronic injury of the sciatic nerve model in mice (Berta et al. 2016; Chen et al. 2018) and suggest the necessity of exploring several the aspects of pain-processing which can be sex dependent.
Other potentially important contributors to physiological and pathological pain are the metabotropic glutamate receptors (mGluR) and glycine transporters such as GlyT1 (Lu et al. 2022; Napier et al. 2012; Tao et al. 2005). Development of selective mGluR antagonists has demonstrated the involvement of the metabotropic receptors in chronic pain modulation (Goudet et al. 2008; Palazzo et al. 2017). In SNL injury models mechanical allodynia is ameliorated by an inhibitor of GlyT1 and by GlyT1 knockdown (Morita et al. 2008). More recently, data provided by Lu et al. demonstrate that the intrathecal anesthetic bupivacaine reduces GlyT1 expression in spinal astrocytes by activating the p-AMPK/BDNF signaling pathway, suggesting that regulation of GlyT1 expression could be a crucial mechanism to modulate the NP mechanisms (Lu et al. 2022). Although glutamate-receptor antagonists have shown effectiveness in reducing pathological pain in animal models, their usefulness in clinical trials has been limited, probably due to their side effects (Collins et al. 2010; Hewitt 2000). Thus, the main targets for effective pharmacological intervention on NP are considered the neuronal circuitry activity and the immune and inflammatory cells. Thus, the main targets for effective pharmacological intervention of NP are considered to be the neuronal circuitry activity and the immune and inflammatory cells (Nakagawa and Kaneko 2010). However, NP is a complex condition and therefore the pharmacological plan should be based on each patient´s clinical history (Jongen et al. 2014; Wu et al. 2021; Zhuo et al. 2011). In this sense, evidence has shown the possible role of non-coding RNAs in modulating the development and progression of NP through the functional expression of several members of transient receptor potential (TRP) and voltage-gated ion (Na+, Ca2+, K+, and Cl−V) channels (Felix et al. 2022). Collectively, all these data suggest the need to identify the molecular pathways and cellular targets as novel potential effectors involved in chronic pain treatment (Chen et al. 2022b; Willemen et al. 2010). In the next section, we will address the novel players in NP management related to non-coding RNAs from a cellular to molecular point of view.
The role of non-coding RNAs in pain pathological mechanisms: special focus on circular RNAs
Non-coding RNAs (ncRNAs) are a class of RNA molecules that typically do not encode proteins but functionally regulate protein expression and many cellular, biochemical and physiological processes. According to their size ncRNAs are classified into small ncRNAs (<200 nucleotides long), including microRNAs (miRNAs) and long ncRNAs (lncRNAs), with a length >200 base pair, and circular RNAs (circRNA) (Hombach and Kretz 2016; St. Laurent et al. 2015). P-element-induced wimpy testis (PIWI-interacting RNAs (piRNAs)), a small ncRNAs once thought to be mainly functioning in germlines (Ozata et al. 2019), is now known to play an essential role in various diseases, including cancer, neurodegenerative diseases, and ageing (Huang and Wong 2021; Su et al. 2020; Wang et al. 2021a). In fact, the piRNA DQ541777 recruits DNMT3a to the CpG islands of the cdk5rap1 promoter, resulting in the methylation of cdk5rap1 and in the regulation of neuropathic pain in the spinal cord after CCI-induced NP. The regulatory effect of piRNA DQ541777 is suggested to be a novel element for future understanding and developing treatments against NP (Zhang et al. 2019). On the other hand, the aberrant expression in neural tissue of piRNAs (whether a disorder cause or consequence) remains a critical issue and its resolution might also facilitate applications for diagnostics and/or therapies in the future (Huang and Wong 2021). Indeed, a dysregulation of ncRNAs has been associated with a variety of neurodegenerative diseases, as well as NP after SCI, where gene-controlled processes can be stimulated or inhibited by ncRNAs (Li et al. 2019; Sámano et al. 2021; Zheng et al. 2022). However, the mechanisms through which those nc-RNAs contribute to the persistence of NP are not fully understood.
In a study using peripheral blood samples of SCI patients with or without NP analysis of lncRNA and miRNA expression levels, revealed a total of 289 lncRNAs and 18197 miRNAs. The co-expression network was investigated by KEGG (Kyoto Encyclopaedia of Genes and Genomes) analysis, where three KEGG pathways, seven genes directly and two lncRNAs were found to be involved in the NP pathway (E2F1, MAX, MITF, CTNNA1, ADORA2B, GRIK3, OXTR, LINC01119, and LINC02447). This suggest that these genes and lncRNAs may play an important role in NP, and might serve as biomarkers of SCI-induced NP (Zhou et al. 2017).
Several ncRNAs have been shown to play a role in the pathogenesis of NP, since they have been identified in pain-related regions (e.g. DRG and spinal cord) of mouse, rat and human nervous system, although the specific effects of ncRNAs in NP remain largely unknown (Jiang et al. 2015; Pan et al. 2017; Ray et al. 2018; Song et al. 2020). Moreover, several reports demonstrated an aberrant expression of ncRNAs (up or downregulated) and the human homologues functions point to them being potential biomarkers for the diagnosis with a crucial role in the pathophysiological process of NP (Kalpachidou et al. 2020; Song et al. 2020).
All these data represented an innovative data integration analysis of a large number of small molecules that microarray technology can disclose with high impact on understanding NP pathogenesis. We are aware that these results are limited to bulk measurements, and recent reports pointed out the need to capture diverse responses of highly heterogeneous samples and even single-cell gene expression profiling for multiple screening at single-cell level (Shin et al. 2019) This approach should be important to decipher the pathway mechanisms of the spinal dorsal horn that are complex and have implications for the pathological enhancement of NP and are also implicated in cell interactions and cell plasticity during pain development (Mauceri 2022). Increasing evidence sheds light on the interactions among ncRNAs and mRNAs in regulating the cellular functions in neurons and glia during NP development (Jin et al. 2018; Song et al. 2020; Xia et al. 2018). Additionally, on the basis of the functional properties of differentially expressed ncRNAs, special focus has been made on better understanding the role and the interactions with a type of lncRNAs, termed circRNA, especially during the NP development (Kalpachidou et al. 2020; Song et al. 2020; Xu et al. 2021b; Zheng et al. 2022).
CircRNAs are expressed from known protein-coding genes (Guo et al. 2014), and at present, four types have been identified: intergenic circRNAs, exo-intron circRNAs (EIciRNAs), and circRNAs from introns and exonic circRNAs (ecircRNAs) (Eger et al. 2018; Zhang et al. 2018).
While pharmacological, nonpharmacological and interventional therapies have been currently used for the management of chronic pain, treatments remain inadequate for a number of patients. In this regard, application of ncRNAs medicine based on miRNAs and lncRNAs to pain prevention or relief represents a new strategy (Jiang et al. 2015; Liu et al. 2017; Roganović and Petrović 2022). Several reports have shown that ncRNAs are involved in inflammatory signaling (Li et al. 2021b), and have indicated new avenues for ncRNAs in diagnostics and therapeutic interventions (Bali and Kuner 2014). Particularly for treating NP, small-molecule targeted therapies using miRNAs or lncRNAs have been explored to edit ncRNA genes with effects that could include disrupting regulatory, structural or functional motifs. Another therapeutic strategy has been targeted to regulate the protein-coding genes at epigenetic, transcriptional or post-transcriptional level (Qureshi and Mehler 2013; Tang et al. 2019). Although some RNA based-therapies have already been approved by the Food Drug Administration (FDA) or the European Medicines Agency (EMA) to treat central or peripheral nervous system diseases (Damase et al. 2021; Winkle et al. 2021), their use in pain research remains limited. This is because dysregulation of ncRNAs has been reported in various regions of different animal models (Bali and Kuner 2014; Li et al. 2021b). Additionally, there may be differences between in vitro and in vivo models and the translational potential is still unknown in humans (Song et al. 2020; Winkle et al. 2021; Wu et al. 2019). Within this framework further work on ncRNAs is needed to clarify their clinical application, efficiency, risks and tolerability. lncRNAs that are the computational construction of interaction between lncRNAs-circRNAs–miRNAs–mRNAs can provide new directions and potential therapeutic targets (Song et al. 2020; Winkle et al. 2021).
To date, circRNAs have been demonstrated to be neuronal specific and to have a close dynamic temporal regulation related to cell death mechanism upon injury (Hanan et al. 2017; Kalpachidou et al. 2020; Ohnishi et al. 2022; Rybak-Wolf et al. 2015). circRNAs are abundant lncRNAs and are well conserved: they consist of a closed continuous loop, which leads to high stability. Most of the circRNAs have been reported to regulate target gene transcription, such as the miRNA expression during the pathological processes in NP (Guo et al. 2020). It is important to emphasize that discrepancies between in vitro and in vivo experiments have arisen. In a recent review, Xu et al. point out that the differences among the differential expression of lncRNAs in many investigations could be due to the lack of specificity of lncRNAs in different NP animal models, and to the source of cells used for each study; these could also be limitations for the development of clinical trials using ncRNAs (Xu et al. 2021b; Zhou et al. 2017). Besides it is still unknown whether hypersensitivity may depend on sexual dimorphism (Xu et al. 2021b).
In recent years, circRNAs have been shown to crosstalk with miRNAs in a negative way, by sponging (Hansen et al. 2013; Panda 2018; Zhang et al. 2018), or in a positive manner, by direct sequence interactions (Piwecka et al. 2017). Thus, Zhou and collaborators have described that the interaction among some lncRNAs, miRNAs, circRNAs, and mRNAs plays an important role during NP pathogenesis in a model of spared nerve injury (SNI). The sequencing and bioinformatics analysis of the expression patterns of ncRNAs has revealed that a total of 134 lncRNAs (12 miRNAs, 188 circRNAs and 1066 mRNAs) is significantly regulated in the spinal cord 14 days after SNI-induced NP. The functional prediction suggests that the regulatory network of lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA are involved during NP pathogenesis, via signalling pathways such as PI3K-Akt, focal adhesion, ECM-receptor interaction, protein digestion and absorption (Zhou et al. 2017). With these data, many investigators have proposed that lncRNAs, including circRNAs are dysregulated during the pathogenesis of NP and several novel points of regulation have been proposed. Particularly, circRNAs due to their biological functions are likely to be used as diagnostic biomarkers in NP or to be considered as novel potential therapeutic targets (Zheng et al. 2022; Zhou et al. 2017).
Cellular and molecular mechanisms regulated by circRNAs to manage pain
In 2017 Cao and colleagues have identified the transcriptome of circRNAs in spinal dorsal horn of a model of CCI neuropathic pain in rats. By circRNAs microarrays they have detected a total of 12,770 circRNAs, from which 469 circRNAs are differentially expressed in CCI rats. These authors have reported 363 circRNAs significantly upregulated and 106 downregulated. Specifically, three circRNAs: rno_circRNA_013779, rno_circRNA_013779, and rno_circRNA_013779, overexpressed over 10 fold in the CCI group. Later, gene ontology (GO) and KEGG pathway analyses have revealed several predicted target genes involved in biological mechanisms, cellular and molecular mechanisms associated with Hippo signaling pathways. Additionally, the circRNA–microRNA–mRNA network analysis has shown the circRNA_008008 and circRNA_013779 as the two largest nodes in the circRNA–microRNA interaction mode. These observations indicate that after CCI insult there are several changes in circRNAs expression in the rat spinal dorsal horn (Cao et al. 2017; Zheng et al. 2022).
Another bioinformatic study revealed that the expression profiling of circRNAs in NP has been associated with several molecular pathways such as PI3K/Akt/mTOR, Wnt/β-catenin, and MAPK signaling by complex sequence of events that are tightly regulated (Salami et al. 2022). In this context the review published by Yash and colleagues has described the landscape of miRNA regulatory network (interactome) and their signal transduction pathways targets, such as IRAK/TRAF6, TLR4/NF-kB, MAPK, TGFb, and TLR5 in NP, which have been proposed as potential biomarkers for diagnosis, prognosis and therapeutic intervention in NP (Gada et al. 2022).
The sponge function of circRNAs by differentially interacting with other miRNAs has been proposed to play a pivotal role during development of NP (Figure 1). For its part, ciRS-7 expression is found in the rat spinal cord dorsal horn of the CCI model of NP. The knockdown of ciRS-7 attenuates microglia activation and expression of pro-inflammatory cytokines, while ciRS-7 targeting miR-135a-5p is associated with NP progress via autophagy. The data suggest that targeting either ciRS-7 or miR-135a-5p could be effective in alleviating NP through suppressing neuroinflammation (Cai et al. 2020). Another circRNA found to be upregulated in the dorsal spinal cord after CCI model in rats, is the circ_0005075: after its knockdown NP behaviours (thermal hyperalgesia and mechanical allodynia) are suppressed and neuroinflammation inhibited through targeting of TNF-α, IL-6, IL-10, and cyclooxygenase (COX)-2. This highlights that the sponging function of cmiR-151a-3p by circ_0005075 depresses NOTCH2 to mediate the neuroinflammation and NP development (Zhang et al. 2021).
A schematic drawing of circRNA biogenesis of several miRNAs against degeneration and development upon SCI. Several circRNA can act as a compensatory mechanism to achieve NP relief by sponge function regulation. Created with Biorender.com.
The effect of circRNAs on microglia and astrocytes following SCI has been documented (Chen et al. 2021), particularly the expression of circPrkcsh shown to be upregulated in astrocytes of mouse injured spinal cord. The circPrkcsh knockout decreases inflammatory response after SCI through the chemokine CC motif ligand 2 (CCL2) expression via miR-488 upregulation (Chen et al. 2022a). In a SCI mouse model the circ-Usp10/miR-152-5p/CD84 axis activates microglial cells, while silencing circ-Usp10 significantly reduces neuronal death of cell line HT22. Thus, circ- Usp10 may promote microglial activation and induce neuronal death by targeting miR-152-5p/CD84 (Tong et al. 2021). The role of circRNA in NP remains poorly understood with a report showing that circSMEK1 facilitates NP inflammation and microglia polarization by modulating miR-216a-5p/TXNIP axis in the NP rat and cell models (Xin et al. 2021). Understanding the glia–glia interactions with sensory neurons together with circRNAs regulation could contribute to identifying the molecular mechanisms of pain signaling, and may provide future therapeutic options to target pain.
Importantly, the circular RNAs expression of both cZRANB1 and circZNF609 is decreased in CCI model in rats. In the study by Wei et al. the upregulation of cZRANB1 alleviates neuropathic pain via modulating Wnt5a/β-Catenin signalling levels by sponging miR-24-3p/LPAR3 axis (Wei et al. 2020). For their part, Li and colleagues showed that circZNF609 promotes inflammatory factors expression, aggravating NP progression via miR-22-3p/ENO1 axis in CCI rat models further confirmed because the functional knockdown of circZNF609 alleviates thermal hyperalgesia and mechanical allodynia through IL6, TNF-α and IL-1 (Li et al. 2020).
On the other hand, in a recent study using microarray analysis and cell cultures from 45 idiopathic scoliosis patients, 25 females and 20 males, has shown that circRNA-CIDN is down-regulated under compression stress. Indeed, the downregulation of extracellular matrix and apoptosis is achieved by sequestering with miR-34a-5p via repressing the silent mating type information regulation 2 homolog 1 (SIRT1) (Xiang et al. 2020). Further evidence for circRNAs role in NP has been obtained by analysing the role of cytoplasmic circAnks1a that acts as a miRNA sponge in miR-324-3p and mediates posttranscriptional regulation of VEGFB expression after sciatic nerve ligation (Zhang et al. 2019). In addition, growing evidence has also shown that miRNAs and circRNAs regulate the occurrence and progression of the intervertebral disc degeneration (IDD) triggered by low back pain (LBP). In a very elegant study Li and collaborators have identified the upregulation of circ-FAM169A in cytoplasm of degenerative nucleus pulposus cells (NPC), which is negatively correlated with the expression of miR-583. Besides that, the prediction analysis has shown that the construction circ-FAM169A-miR-583-mRNAs network is related to the extracellular matrix metabolism and apoptosis, where miR-583 negatively regulates Sox9 mRNA and other proteins in NPCs. With these data, Li et al. suggests that the function of circ-FAM169A as ceRNA is to sponge miR-583, which in turn will modulate the pathogenesis of IDD. Although circ-FAM169A-miR-583-mRNAs was identified as key network involved in IDD, the significant role of the circ-FAM169A-miR-583 requires further investigation (Li et al. 2021a). Recent evidence obtained from 15 patients suffering from IDD and low back pain, has investigated the expression and sponge function of circRNAs in spinal tissues in vivo and in vitro. Specifically, the biological function and differential expression of circRNA are upregulated (circ-4099, circRNA_104670, circ-FAM169A, and circ-TIMP2) and/or downregulated (circSEMA4B, circ-GRB10, circVMA21, and circRNA-CIDN) suggesting a key role in several processes such as apoptosis, proliferation, and senescence by acting as compensatory mechanism against degeneration and pain development. Indeed, more evidence obtained from patients suffering from IDD and low back pain, points to the biological function of ccirc_0040039 and circ_0004354 in modulating inflammatory response, growth inhibition, and extracellular matrix components and, therefore, a crucial role in disc degeneration. These data have demonstrated, by bioinformatics analysis of microarray dataset, that the mechanism of these circRNAs is to induce mixed apoptosis and inflammatory response due to a competitive adsorption of miR-345-3p (Li et al. 2022). Finally, the gene expression profile of circRNA in certain regions of post-mortem brain tissue of 42 Parkinson’s disease patients was recently analysed (Wu and Kao 2016). This report shows the modulation of several pathways such as neurodegeneration and synaptic transmission, but probably by cooperating with RNA processing of gene products to exacerbate or limit neurodegeneration. Indeed, the cooperation of different cells types, that are known to modulate neuronal functions, may exacerbate damage under diverse insults (Wu and Kao 2016). In summary, this report shows that circRNA probably operates not only by sponging miRNAs but also contributes to complex events involved in altered checkpoints (circularized splicing, miRNA regulation, and protein decline) which may amplify the functional impact alongside the stoichiometry of those molecules (Hanan et al. 2020). circRNAs are increasingly recognized as important regulatory molecules of various cellular and molecular processes (Xu et al. 2021a). Dysregulated functions have been reported during pain development and in response to SCI (Jiang et al. 2022). Because circRNAs are highly stable and usually expressed in a tissue, cell and disease type-specific manner, they have been currently proposed and explored as potential therapeutic targets (Ma et al. 2020). In this context, gain-or-loss of function approaches are performed using circRNAs expression plasmids or RNA-interference-based strategies. In particular, spinal injection of circAnks1a siRNA has been found to alleviate pain-like behavior in rats (Zhang et al. 2019). circHIPK3 shRNA can reduce NP in diabetic rats (Wang et al. 2018), and the circRNA.2837 inhibitor decreases pain in the sciatic nerve injured rat model by sponging miR-34 and inducing autophagy (Zhou et al. 2018). circRNAs have unique expression signatures and play crucial roles in transcriptional and posttranscriptional mechanisms, leading to the development of circRNA-based therapeutics.
Conclusions
NP as a consequence of SCI is a condition with currently limited effective treatment. Unfortunately, patients describe NP as an unbearable condition with long-term effects that affect their quality of life. At present, the research on NP related to SCI is mostly concentrated in rodent animal models, and recent studies have provided data in which cellular and molecular mechanisms are induced by many dysregulated gene expressions, with the lncRNAs as the regulatory factors proposed to play a relevant role during the pathomechanisms involved in NP. Particularly, growing evidence has emerged demonstrating dysregulation of several circRNAs involved in NP development (Figure 1). circRNAs have gained pathophysiological relevance, because of their synthesis by a noncanonical splicing event, their stability for up to 48 h in cells, and their specificity function as sponge of miRNAs. In this paper, we summarize recent data concerning circRNAs modulation by sponging miRNAs and suppressing or promoting cellular and molecular pathways and the interaction with mRNAs and proteins (Figure 2). Indeed, up to today, management of NP has been concentrated to reduce the toxicity and addictive potential; hence, circRNAs regulation may unveil certain molecular mechanisms involved in NP (hyperalgesia, allodynia and spontaneous pain) and can be used as novel potential effectors for chronic pain treatment. Nevertheless, in this review we have highlighted recent data supporting the idea of circRNAs acting as reliable biomarkers to manage NP after SCI. Therefore, translational studies using expression profile analysis of circRNAs, probably from body fluids, point out the importance for novel pharmacological treatments with high therapeutic value. Altogether, these data demonstrate that circRNAs are likely to be used as potential diagnostic in NP or to be considered as novel potential therapeutic targets after spinal injuries. Finally, all of this knowledge supports the proposal that circRNAs could be good therapeutic options for biomarkers and/or novel targets to NP relief and treatment, since unlike other treatments, they do not show toxicity or potential addiction.
A schematic diagram of circRNA sponge functional regulation due to several proteins interactions and the main cellular processes involved in NP modulation, such as apoptosis, proliferation, and senescence. Created with Biorender.com.
Funding source: Ministry of Science, Technology and Productive Innovation of Argentina through the Fund for Scientific and Technological Research
Award Identifier / Grant number: PICT-2020-SERIEA-00928
Award Identifier / Grant number: PICT-2020-SERIEA-00030
Funding source: Departamento de Ciencias Naturales (DCN), de la División de Ciencias Naturales e Ingeniería (DCNI) de la UAM-Cuajimalpa
Funding source: Croatian Science Foundation grant
Award Identifier / Grant number: IP-2016-06-7060
Funding source: Universidad Austral, CONICET
Funding source: UniRi research
Award Identifier / Grant number: prirod-sp-20-38-2687
Award Identifier / Grant number: uniri-biomed-18-258-1427
Funding source: IBRO Collaborative Research Grant
Acknowledgment
The authors would like to thank Prof Andrea Nistri and Dr. Carly McCarthy for the helpful comments on the manuscript.
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Author contributions: GM and CS contributed to the conception of principal ideas, wrote the first draft of the manuscript and performed the graphic design. MM and MFC wrote some sections of the manuscript, and thoroughly proofread the last version. All authors contributed to the article and approved the submitted version.
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Research funding: GM was supported by Universidad Austral, CONICET, Ministry of Science, Technology and Productive Innovation of Argentina through the Fund for Scientific and Technological Research (FONCYT, PICT-2020-SERIEA-00928) and IBRO Collaborative Research Grant. MFC was supported by Universidad Austral, CONICET and the Ministry of Science Argentina (PICT-2020-SERIEA-00030). MM was supported by Croatian Science Foundation grant IP-2016-06-7060 and UniRi research support uniri-biomed-18-258-1427 and prirod-sp-20-38-2687. CS was supported by the Departamento de Ciencias Naturales (DCN) de la División de Ciencias Naturales e Ingeniería (DCNI) de la UAM-Cuajimalpa (Divisional Project 47301025).
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Conflict of interest statement: The authors declare no conflict of interest.
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