The emerging power and promise of non-coding RNAs in chronic pain

Zhang, Changteng; Gao, Rui; Zhou, Ruihao; Chen, Hai; Liu, Changliang; Zhu, Tao; Chen, Chan

doi:10.3389/fnmol.2022.1037929

REVIEW article

Front. Mol. Neurosci., 03 November 2022

Sec. Pain Mechanisms and Modulators

Volume 15 - 2022 | https://doi.org/10.3389/fnmol.2022.1037929

This article is part of the Research Topic Focus on Chronic Pain: Neuropathological Mechanism, Clinical Diagnosis and Treatment View all 26 articles

The emerging power and promise of non-coding RNAs in chronic pain

$\r\nChangteng Zhang,&#x;$ Changteng Zhang^1,2†

Rui Gao^1,2*†

Ruihao Zhou^1,2

Hai Chen^3,4

Changliang Liu^1,2

Tao Zhu^1,2

Chan Chen^1,2*

¹Department of Anesthesiology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, Chengdu, China
²Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
³Department of Respiratory and Critical Care Medicine, West China Medical School/West China Hospital, Sichuan University, Chengdu, China
⁴Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China

Chronic pain (CP) is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage lasting longer than 3 months. CP is the main reason why people seek medical care and exerts an enormous economic burden. Genome-wide expression analysis has revealed that diverse essential genetic elements are altered in CP patients. Although many possible mechanisms of CP have been revealed, we are still unable to meet all the analgesic needs of patients. In recent years, non-coding RNAs (ncRNAs) have been shown to play essential roles in peripheral neuropathy and axon regeneration, which is associated with CP occurrence and development. Multiple key ncRNAs have been identified in animal models of CP, such as microRNA-30c-5p, ciRS-7, and lncRNA MRAK009713. This review highlights different kinds of ncRNAs in the regulation of CP, which provides a more comprehensive understanding of the pathogenesis of the disease. It mainly focuses on the contributions of miRNAs, circRNAs, and lncRNAs to CP, specifically peripheral neuropathic pain (NP), diabetic NP, central NP associated with spinal cord injury, complex regional pain syndrome, inflammatory pain, and cancer-induced pain. In addition, we summarize some potential ncRNAs as novel biomarkers for CP and its complications. With an in-depth understanding of the mechanism of CP, ncRNAs may provide novel insight into CP and could become new therapeutic targets in the future.

Introduction and chronic pain overview

Chronic pain (CP) is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage lasting longer than 3 months (Treede et al., 2015; Raja et al., 2020). Approximately 20% adults suffer pain and another 10% adults are diagnosed with CP worldwide each year (Goldberg and McGee, 2011). Patients with CP are often characterized as having allodynia (innocuous stimulus causing pain), hyperalgesia (noxious stimulus triggering an amplified response), and spontaneous pain (Woolf and Salter, 2000). Several factors are associated with the severity of CP, mainly including age, gender, genetics, ethnicity, cultural background, smoking, alcohol, physical activity, mental health, surgical and medical interventions, and even other attitudes and beliefs about pain, etc. (Mills et al., 2019). Moreover, comorbidities and complications are two difficult problems of CP. Patients with CP often have an increased co-occurrence of depression, cardiovascular disease, clinical insomnia, etc. (Jank et al., 2017; Macfarlane et al., 2017; van Hecke et al., 2017). Several common types of CP are summarized in this review, such as neuropathic pain (NP), complex regional pain syndrome (CRPS), inflammatory pain (IP), and cancer-induced pain (CIP) (Treede et al., 2019). Thereinto, the etiology of chronic NP can be divided into peripheral nerve lesions [such as peripheral nerve injury (PNI)-induced NP, diabetic NP (DNP), etc.] and central nerve lesions [such as spinal cord injury (SCI)] (Treede et al., 2019).

The mechanisms underlying CP have been explored for several decades, mainly including central sensitization, neuroinflammation, oxidative stress, etc. (Ji et al., 2018; Kaushik et al., 2020). However, the pathogenesis of CP has not been completely elucidated. Although several analgesic treatments are available, they are often hampered by side effects or limited efficacy (Sisignano et al., 2019). Elucidating the pathogenic mechanisms of CP may help seek novel specific biomarkers and efficient therapies for controlling the symptoms of CP. Notably, non-coding RNAs (ncRNAs) are altered greatly in both clinical research and pre-clinical models of CP and constitute a regulatory transcriptome network in the pathogenesis of CP (Ciszek et al., 2015; Peng et al., 2017; Du et al., 2022). Multiple ncRNAs are differentially expressed in the animal models of CP (Li et al., 2021b) and are strongly related to various mechanisms, such as pain-related signaling pathways, receptors, cytokines, cell processes, ion channels, and exosomes in cell-to-cell communications (Wang Z. et al., 2018; Xiang et al., 2019; Ma et al., 2021; Felix et al., 2022; Liu et al., 2022; Figure 1).

FIGURE 1

Figure 1. Non-coding RNAs (ncRNAs) and their regulatory mechanism in chronic pain: ncRNAs can participate in pain regulation through various mechanisms. Some common and key mechanisms mainly include pain-related signaling pathways; pain-related receptors and targets; regulation of cytokines release; some cell processes (cell migration, autophagy and apoptosis etc.); exosomal ncRNAs crosstalk between cells and ncRNAs targeting ion channels related to chronic pain. Akt, V-akt murine thymoma viral oncogene homolog; Cav, voltage-gated calcium; IL, interleukin; MAPK, mitogen-activated protein kinases; Kv, voltage-gated potassium channel; Nav, voltage-dependent sodium; ncRNAs, Non-coding RNAs; PI3K, phosphatidylinositol-3-kinase; TLRs, toll-like receptors; TNF, tumor necrosis factor; TRPV1, transient receptor potential vanilloid 1.

This review aims to summarize the recent evidence about the potential role of ncRNAs in CP. Understanding their functions may help to reveal the complex pathogenic mechanisms in CP and identify new potential diagnostic biomarkers and therapeutic targets.

General aspects of non-coding RNAs

Non-coding RNAs are defined as RNAs that are unable to translate into proteins (Beermann et al., 2016). Generally, ncRNAs are divided into two categories according to their sequence length: (I) small ncRNAs (few to 200 nt), including microRNA (miRNA), ribosomal, small nuclear, piwi-interacting, and small interfering RNA; and (II) long ncRNA (lncRNA) (longer than 200 nt) (Beermann et al., 2016; Hombach and Kretz, 2016). We mainly introduce some general aspects of the three common types of ncRNAs: miRNA, circular RNA (circRNA), and lncRNA as follows (Esteller, 2011; Westholm and Lai, 2011; Kristensen et al., 2019; Figure 2).

FIGURE 2

Figure 2. Main functions of three types of non-coding RNAs. (A) General functions of microRNA (miRNA). Unwinding of the miRNA via Argonaute, and transactivation response RNA-binding protein (TRBP)-dependent loading into the RNA-induced silencing complex (RISC). Binding of target mRNAs to miRNAs in RISC can result in translation repression or degradation of the mRNA. MiRNA and RISC can translocate to other cells. The RISC contains RNA-binding proteins including protein kinase RNA activator, TRBP and Dicer. (B) General functions of circular RNA (circRNA). CircRNA can act as miRNA sponge and protein complex stabilization. CircRNAs have other functions (including promoting cell proliferation etc.). (C) General functions of Long non-coding RNA (lncRNA). LncRNA can inhibit miRNA and act as transcriptional regulator. LncRNA participates in scaffolding complexes. The lncRNA possesses different domains that bind distinct effector molecules. The lncRNA can bind its multiple effector partners at the same time, which may have transcriptional activating or repressive activities, together in both time and space. Ago, Argonaute; circRNAs, circular RNAs; lncRNAs, long non-coding RNAs; miRNAs, microRNAs; RISC, RNA-induced silencing complex; TRBP, transactivation response RNA-binding protein.

MicroRNAs, endogenous and single-stranded RNAs ranging between 21 and 25 nucleotides in length, widely regulate gene expression, and more than 60% of genes are targets of miRNAs (Friedman et al., 2009). MiRNA has uridine at its 5′-end and is partially complementary to the 3′-end untranslated regions of the messenger RNA (mRNA). MiRNAs are produced by two RNase III proteins, Drosha and Dicer (Vishnoi and Rani, 2017). Pre-miRNAs are cleaved and processed by Drosha in the nucleus and guided to the cytoplasm (Ma et al., 2008; Westholm and Lai, 2011). Then, the pre-miRNA unwinds and one strand is incorporated into the RNA-induced silencing complex which is composed of Dicer, the double-stranded RNA-binding protein TRBP, and Argonaute2 proteins, ultimately resulting in translation repression or degradation of the mRNA (Gregory et al., 2005; Wu et al., 2006). The critical roles of miRNAs in animal models of CP, such as the severe dysregulation of miRNAs in the dorsal root ganglion (DRG) and the spinal cord regions, have been reported in many studies (Bali et al., 2013; Peng et al., 2017; Sakai et al., 2017).

Circular RNAs are generally produced through back-splicing or exon skipping of pre-mRNAs, while a single genomic location can generate multiple types of circRNAs. CircRNAs are notable for their continuous closed-loop structure, named a “back-splicing” structure, which is primarily formed through the junction of a downstream 3′ splice site with an upstream 5′ splice site (Zhang et al., 2016). Due to these structures, circRNAs are abnormally stable for exonucleases and are widely involved in various life processes such as cell proliferation, differentiation, and apoptosis (Haque and Harries, 2017). CircRNAs play key roles in mRNA stability and function through their activities as miRNA sponges, translation modulators, protein complex stabilization, and biomarkers (Hansen et al., 2013). CircRNAs are stable in the human bloodstream under physiological or pathological conditions and may be a potential biomarker easily obtained for clinical CP patients in the future (Vea et al., 2018).

Long non-coding RNAs have more than 200 nucleotides and can interact with proteins, DNAs, and multiple RNAs (Ulitsky and Bartel, 2013). LncRNAs lack protein-coding potential and often harbor a poly-A tail and can be spliced, which has been shown to play vital roles in a variety of biological processes such as translational inhibition, transcriptional silencing, promoter-specific gene regulation, X-chromosome inactivation, imprinting, maintenance of nuclear architecture and modulation of multiprotein complexes (Lee, 2009; Ponting et al., 2009; Statello et al., 2021). An estimated abundance of 5,400 to more than 10,000 lncRNA transcripts has been reported in humans (Jia et al., 2010; Djebali et al., 2012; Lorenzi et al., 2021) and several studies have shown that lncRNAs contribute to the occurrence of CP in some pre-clinical models by targeting pain-associated genes or other downstream molecules and increasing neuronal excitability in DRG primary sensory neurons (Zhao et al., 2013; Du et al., 2022).

Several factors are associated with expression of ncRNA. Current evidence has demonstrated that common traits, including age, sex, smoking, body mass, and physical activity, can influence circulating small ncRNA expression levels (Rounge et al., 2018), among which aging is a strong factor. For example, a previous study has analyzed miRNAs from the whole blood of 5,221 individuals and found that 127 of 150 miRNAs are affected by age (Huan et al., 2018). In addition, different exercise training programs greatly alter ncRNAs. Researchers have identified 204 differentially expressed lncRNAs (DELs) from untrained young individuals after 12 weeks of high-intensity interval training, whereas 43 DELs are identified after resistance training (Bonilauri and Dallagiovanna, 2020).

In this review, we provide an overview of the recent research progress and specific roles of ncRNAs in CP and focus on the alterations of ncRNAs reported mainly in the blood samples, DRG, spinal cord dorsal horn (SDH), and injured peripheral nerves of animal models and patients suffering CP.

Non-coding RNAs: Insights into the molecular mechanism of chronic pain

Peripheral neuropathic pain-associated with peripheral nerve injury

Neuropathic pain affects 8% of adults worldwide and is commonly caused by somatosensory system lesions or diseases, such as PNI (Colloca et al., 2017; Finnerup et al., 2021). PNI is a major onset cause of NP in adults, characterized by allodynia and pain hypersensitivity, and accompanied by ncRNAs alterations in the DRG or peripheral blood in patients (Arthur-Farraj et al., 2017; Hu et al., 2021). An increasing number of researchers have focused on the potential of ncRNAs as biomarkers in PNI-induced NP (Table 1).

TABLE 1

Table 1. Non-coding RNAs in periphery neuropathic pain (including PNI and DNP).

MicroRNAs

Peripheral nerve injury leading to NP is usually accompanied by miRNA alterations in DRG or other tissues, which has been proven to be associated with the severity of pain hypersensitivity (Adilakshmi et al., 2012; Chang et al., 2017; Wang Y. et al., 2021). MiRNAs bind to the 3′-untranslated region of target mRNAs, causing mRNA splicing and destabilization (Bartel, 2009). This is a crucial mechanism by which miRNAs are involved in NP. MiR-124-3p is downregulated in the DRG and SDH in a spared sciatic nerve injury (SNI)-induced NP rat model, leading to upregulation of Egr1 (Jiang et al., 2021). Analogously, miR-206-3p is decreased in the DRG of chronic constriction injury (CCI) rats and histone deacetylase 4 (HDAC4) is identified as a potential target of miR-206-3p. Intrathecal injection a lentivirus encoding miR-206-3p (LV-miR-206-3p mimic) upregulates the level of miR-206-3p in DRG of rat and alleviates NP induced by PNI (Wen et al., 2019). In addition, accumulative studies have shown that miR-223, miR-144, miR-140-3p, miR-122-5p, miR-30b-5p, and miR-340-5p, are highly decreased in the CCI model and verify their roles in the development of NP (Gao et al., 2019; Zhang X. et al., 2020; Cheng et al., 2021; Wan et al., 2021; Zhu et al., 2021; Liao et al., 2022). However, some miRNAs contributed to NP are contrary to the conventional trend. Upregulation of miR-30c-5p is observed in the DRG, spinal cord, plasma, and cerebrospinal fluid (CSF) of SNI rats, and is robustly consistent with the severity of allodynia (Tramullas et al., 2018).

Furthermore, the regulation of voltage-gated channels in DRGs by miRNAs has been considered another critical mechanism in CP in recent years. Following PNI-induced NP in rats, for instance, voltage-dependent sodium (Nav) 1.7 encoded by the SCN9A gene in the afferent fiber is proven to be involved in the development of NP (Xue et al., 2021). Interestingly, intrathecal administration of miR-30b agomir, chemically modified double-strand miR-30b mimic, shows an obvious decrease in Nav1.7 in DRG neurons and alleviates pain behaviors remarkably (Shao et al., 2016). The above evidence has indicated the regulatory effect of miRNAs on voltage-gated sodium channels in DRGs. In addition to miR-30b, upregulation of miR-137 suppresses the expression of voltage-gated potassium channel (Kv) Kv1.2 and increases mechanical allodynia and thermal hyperalgesia in CCI rats (Zhang J. et al., 2021). Downregulation of miR-137 restores the abnormal Kv currents and excitability in DRG neurons and thus attenuating NP. Moreover, voltage-gated calcium channels related to CP are also regulated by miRNA. MiR-34c-5p could bidirectionally regulate voltage-gated calcium (Cav) 1.2 channels, which proves that they can interact with each other to regulate hyperalgesia (Favereaux et al., 2011).

In addition to acting on voltage-gated channels, miRNAs also interact with numerous receptors in PNI-induced NP. Taking toll-like receptors (TLRs) as a common example, the expression of TLR8 is highly increased in IB4⁺ DRG neurons in a spinal nerve ligation (SNL) model, and inhibition of TLR8 alleviates SNL-induced pain (Zhang et al., 2018). Moreover, miRNAs interact with TLR8 highly associated with NP. Mechanistically, the miR-21-TLR8 signaling axis is identified as an important target in the SNL model (Zhang et al., 2018). TLR5 is also observed to be upregulated in bilateral CCI rats regulated by miR-217 (Jiang et al., 2019). Downregulation of the level of miR-217 exerts an inhibition effect of TLR5 through suppressing neuroinflammation and alleviates NP in vivo ultimately. Additionally, the C-X-C motif chemokine receptor (CXCR) is reported to be involved in the regulation of NP. Dong et al. (2021) have proved that the C-X-C motif chemokine ligand-12 (CXCL12)-CXCR4 pathway is regulated by miR-130a-5p in the development of NP. MiR-130a-5p mimics can attenuate CCI-induced NP in vivo by inhibiting the activation and inflammatory response of astrocytes, as well as inactivating CXCR4 and its downstream targets, such as Rac1 and nuclear factor-κB (NF-κB), etc. (Dong et al., 2021). Further study might be performed to explore more novel receptors contributing to the pathogenesis of PNI related to NP, providing for more strategies to treat NP.

The crosstalk between immune system and nervous system may be a novel pathogenic mechanism (Pinho-Ribeiro et al., 2017). It has been reported that exosomes and its cargos, including miRNAs, mediate the crucial crosstalk between different cells, organs, or systems, and are involved in the regulation of NP (Simeoli et al., 2017; D’Agnelli et al., 2020). Simeoli et al. (2017) have verified that exosomal miR-21-5p, as one of the cargos of sensory neuron-derived exosomes, is released after capsaicin activation of transient receptor potential vanilloid 1 (TRPV1) receptor in cultured DRG. In vivo, intrathecal injection of miR-21-5p antagomir, the inhibitor of miR-21-5p, attenuates neuropathic hypersensitivity and reduces the extent of inflammatory macrophage recruitment in the DRG. In brief, exosomal cargos play critical roles in sensory neuron–macrophage communication after damage to the peripheral nerve, and similar remote communication in the NP deserves further investigation.

Circular RNAs

Accumulative studies have also shown that circRNAs are significantly altered in the SDH in rats with NP. Bioinformatics analysis has shown that the expression levels of three circRNAs, circRNA_013779, circRNA_008008, and circRNA_003724, are increased more than 10 fold in the SDH of the CCI model compared with the control group (Cao et al., 2017), indicating that these three circRNAs are involved in the pathogenesis of NP. In addition, circRNA_008008 and circRNA_013779, as the two largest nodes in the circRNA-miRNA interaction network, can interact with eight miRNAs (Cao et al., 2017).

Mechanistically, current studies have found that circRNAs regulate pain by acting as miRNA sponges and through the circRNA-miRNA-downstream molecular axis. CIRCZNF609 acts as miRNA sponge to inhibit the expression of miR-22-3p, which alleviates mechanical allodynia and thermal hyperalgesia levels through regulation of the expression of Tumor Necrosis Factor-alpha (TNF-α), interleukin-1 (IL-1), and IL-6 in L4-L6 spinal cord tissue of CCI rats (Li et al., 2020). CircRNA.2837 attenuates nerve damage by regulating autophagy by targeting the miR-34 family (including miR-34a, miR-34b, and miR-34c) (Zhou et al., 2018). Besides, some other circRNAs are also involved in PNI through a similar mechanism, such as circ_0005075 as miR-151a-3p sponge in CCI rats (Zhang J. Y. et al., 2021), circ-Ankib1 as miR-423-5p, miR-485-5p, and miR-666-3p sponges in PNI (Mao et al., 2019) and ciRS-7 as the miR-135a-5p sponge in CCI rats (Cai et al., 2020).

In addition, circRNAs play roles in regulation of various pain-related signaling pathways. Several studies have performed Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, showing that the Hippo signaling pathway, MAPK signaling pathway, and endocytosis are the most key pathways related to NP (Li N. et al., 2013; Chen and Lu, 2017; Huang et al., 2017). CircRNAs alleviate or aggravate pain by controlling signaling pathways, ultimately affecting the associated inflammatory levels. For example, circ_0005075 affects the expression level of Notch2 by inhibiting the level of miR-151a-3p, eventually leading to changes in cyclooxygenase-2 (COX-2), IL-6, TNF-α, and other cytokines in the CCI model (Zhang J. Y. et al., 2021). Previous studies have demonstrated that Notch signaling is activated, mediating mechanical hyperalgesia induction and maintenance in a rat model of NP (Xie et al., 2015). Additionally, circRNA ZRANB1 mediates the Wnt5a/β-catenin signaling pathway to aggravate NP by acting on the miR-24-3p/LPAR3 axis (Wei et al., 2020). However, regulation of circRNAs in the complex signaling pathway network of NP is still very limited, and further studies are needed to elucidate the downstream pathways participating in the regulation of pain.

Long non-coding RNAs

Similar to miRNAs and circRNAs, lncRNAs also play roles in regulating the process of PNI. Since there is abundant evidence that includes lncRNAs in PNI, we mainly focus on the common downstream targets related to PNI regulated by lncRNAs in the latest findings. However, current research on lncRNA with its targets related to NP is not in-depth. Most current research mainly focuses on the mechanism of the lncRNA/miRNA/target axis. LncRNAs can directly bind to several targets, such as many receptors, ligands or enzyme, and participate in the pathogenesis of PNI-induced NP. Although receptors are of various types, they can be roughly divided into ion channel receptors and non-ion channel receptors. The typical ionic receptors are the P2X receptor and EPHB1-NMDA. The other targets mainly include CXCL, Janus kinase (JAK), brain-derived neurotrophic factor (BDNF), high mobility group box-1 (HMGB1), cyclin-dependent kinases (CDKs) and programmed cell death factor-4 (PDCD4), etc.

P2X receptors, members of an ATP-gated ion channels family, are widely involved in CP regulated by ncRNAs (Xiong et al., 2019). LncRNA MRAK009713 is markedly increased and interacts with P2X₃ to enhance mechanical and thermal hyperalgesia in CCI rats (Li et al., 2017). LncRNA LOC100911498 plays a key role in the pathophysiological process of NP and LOC100911498 siRNA can block P2X₄Rs-mediated p38MAPK activation and BDNF release, attenuating NP in rats (Tang et al., 2021). Additional evidence of ion channel receptors involved in PNI is that overexpression of lncRNA uc.153 in SC increases NP by targeting miR-182-5p and subsequent modulation of EphB1-NMDA receptors (Zhang C. et al., 2020).

On the other hand, some targets related to inflammation and the cell cycle are identified to be related to PNI-induced NP regulated by various lncRNAs. HMGB1, as a critical target in NP, is expressed in multiple cells (Andersson et al., 2002), and can promote neuroinflammation and NP in animal models (Wen et al., 2021). Diverse lncRNAs, such as lncRNA FIRRE, lncRNA NEAT1, and lncRNA MALAT1, can regulate HMGB1 and are involved in PNI-induced NP (Xia et al., 2018; Ma et al., 2020; Wen et al., 2021). Inhibition of lncRNA MALAT1 reverses the abnormal increasing expression level of HMGB1 caused by CCI surgery in rats, which attenuates the development of NP and neuroinflammation (Ma et al., 2020). The LncRNA MALAT1/miR-129-5p/HMGB1 axis is confirmed to play a critical role. Another study has reported that downregulation of lncRNA FIRRE suppresses the secretion of microglial cell-derived proinflammatory cytokines and reduces NP by also suppressing HMGB1 expression (Wen et al., 2021). Additionally, the lncRNA NEAT1/miR-381/HMGB1 axis highly contributes to PNI-induced NP (Xia et al., 2018).

Cyclin-dependent kinases, cell cycle-related proteins, have also been shown to be engaged in pain-related behavior (Yokoyama et al., 2020). The lncRNA PKIA-AS1 directly regulates the expression and function of CDK6 in SNL-induced NP, exerting an effect on maintaining neuroinflammation and NP (Hu et al., 2019). Inhibition of lncRNA PKIA-AS1 decreases the expression of CDK6 and alleviates SNL-induced NP (Hu et al., 2019). The lncRNA SNHG1 induces NP by directly regulating CDK4 levels (Zhang J. Y. et al., 2020). WNT5A, a member of the WNT family, is reported to be related to pain behaviors, and inflammatory responses and could sensibilize spinal nerves in rat models of NP (Simonetti and Kuner, 2020). The lncRNA CRNDE/miR-146a-5p/WNT5A axis plays a central role in rats with CCI-induced NP (Zhang Q. et al., 2021). CXCL has the normal physiological function of inducing directed chemotaxis of nearby reactive cells and is also believed to play a role in peripheral NP (Braga et al., 2020). Knockdown of LncRNA SNHG5 in the DRG of SNL mice alleviates NP and inhibits the activation of astrocytes and microglia by targeting the miR-154-5p/CXCL13 axis (Chen et al., 2020). The JAK-STAT pathway is an original signal transduction pathway shared by multiple cytokines (Dominguez et al., 2008; Wang et al., 2016a) and has been reported to be regulated by lncRNAs in PNI-induced NP. Downregulation of lncRNA DILC in the spinal cord attenuates NP through SOCS3-induced suppression of the JAK2/STAT3 pathway while increasing the viability of primary microglia, suppressing apoptosis and inhibiting the production of interleukin (IL)-6 and IL-1β in microglia (Liu Y. et al., 2020). STAT3 is also regulated by lncRNA XIST. Increasing the lncRNA XIST in the spinal cord can contribute to CCI-induced NP in rats by downregulating miR-544 and upregulating STAT3 (Jin et al., 2018). The lncRNA Linc00052/miR-448/JAK1 axis also plays a key role in SNL-induced NP (Wang L. et al., 2020). PDCD4, a translation factor that binds to eIF4A, is regulated by various lncRNAs under different pathological conditions. For instance, miR-155 regulate the inflammatory response through SOCS1–STAT3–PDCD4 in atherogenesis (Ye et al., 2016) and is recently found its concrete role in NP. Overexpression of lncRNA DGCR5 in the spinal cord attenuates NP by sponging miR-330-3p and targeting PDCD4 in CCI rats (Peng et al., 2019). Zeste homolog 2 (EZH2), a contributor to microglial activation and NP, can bind to lncRNAs. The LncRNA Lncenc1 contribute to NP by targeting EZH2 and downregulating the brain angiogenesis inhibitor 1 (BAI1) gene in mouse microglia (Zhang Z. et al., 2021). Furthermore, upregulation of lncRNA GAS5 in the spinal cord decreases pain behaviors by targeting miR-452-5p/CELF2 (Tian et al., 2020).

In addition to the receptors above, amniotic aquaporins (AQP), special channel proteins with roles in PNI-induced NP, has been reported recently. Knockdown of AQP9 promotes the development of NP, and further investigation have revealed that the lncRNA MALA T1/miR-154-5p/AQP9 axis acts as a novel target for NP (Wu J. et al., 2020). In summary, multiple lncRNAs can bind to the same receptor, while a single lncRNA can target numerous receptors in the development of PNI-induced NP. More research is needed to elucidate the huge network between lncRNAs and their receptors.

Peripheral neuropathic pain-associated with diabetic neuropathic pain

Diabetic neuropathic pain is a general complication of diabetes mellitus (DM), and patients with DNP suffer various degrees of pain (Feldman et al., 2017). Oral treatment is the most frequent topical treatment for DNP, but its use is often limited by systemic side effects (Yang et al., 2019). Since a large population suffers from DM worldwide with a high risk of DNP (Sloan et al., 2018), we must seek better treatment to alleviate DNP. Much evidence has shown that ncRNAs are dysregulated in DNP (Table 1) and have the potential to be a novel strategy (Figure 3).

FIGURE 3

Figure 3. Distribution of dysregulated non-coding RNAs (ncRNAs) with the respective associated targets in diabetic neuropathic pain (DNP): ncRNAs (including microRNA, circular RNA, and long non-coding RNA) can participate in the development of DNP through various targets and mechanisms. NcRNAs displays different expressions in DRG, spinal cord and sciatic nerve of DNP models in DNP. DRG, dorsal root ganglion; HMGB1, high mobility group box-1; IL, interleukin; MAPK, mitogen-activated protein kinases; Nrf2, nuclear factor erythroid 2-related factor 2; RAP1A, Ras-associated protein-1 A; TNF, tumor necrosis factor; TRPV1, transient receptor potential vanilloid 1.