Abstract

Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain in general, and members of the non-coding RNA (ncRNA) family, specifically the short, 22 nucleotide microRNAs (miRNAs) and the long non-coding RNAs (lncRNAs) act as master switches orchestrating both immune as well as neuronal processes. Several chronic disorders reveal unique ncRNA expression signatures, which recently generated big hopes for new perspectives for the development of diagnostic applications. lncRNAs may offer perspectives as candidates indicative of neuropathic pain in liquid biopsies. Numerous studies have provided novel mechanistic insight into the role of miRNAs in the molecular sequelae involved in the pathogenesis of neuropathic pain along the entire pain pathway. Specific processes within neurons, immune cells, and glia as the cellular components of the neuropathic pain triad and the communication paths between them are controlled by specific miRNAs. Therefore, nucleotide sequences mimicking or antagonizing miRNA actions can provide novel therapeutic strategies for pain treatment, provided their human homologues serve the same or similar functions. Increasing evidence also sheds light on the function of lncRNAs, which converge so far mainly on purinergic signalling pathways both in neurons and glia, and possibly even other ncRNA species that have not been explored so far.

Introduction

Human neuropathic pain disorders are difficult to diagnose and treat due to their diversity, which even increases with the development of chronic pain. The most frequent neuropathic pain disorder is diabetic painful neuropathy (DPN), which occurs as a common complication of diabetes mellitus [1,2]. Although good control of blood glucose levels can reduce the incidence of DPN mainly in Type I diabetes, more than half of the patients still develop DPN for which only symptomatic therapy of low to moderate efficacy is available to date [3]. Neuroinflammatory signatures have been identified as critical components of DPN but its complex pathogenesis is still incompletely understood [3,4]. Pathological neuro-immune communication has, likewise, been associated with other painful neuropathies such as neuropathic pain occurring in up to 50% of patients experiencing traumatic nerve injury as a consequence of accidents, warfare or surgical procedures [5–7]. Also the neurogenic complex regional pain syndrome (CRPS), an enigmatic complication of bone fracture or tissue injury, is associated with neuro-inflammatory deficits [8]. In the majority of patients symptoms largely resolve, however in 30% of cases the pain persists or even intensifies [9]. The beneficial effect of glucocorticosteroids in acute CRPS points towards pathophysiological mechanisms associated with neuro-immune dysfunction [9–11].

Such neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain in general, and members of the non-coding RNA (ncRNA) family, specifically the short, 22 nucleotide microRNAs (miRNAs) as regulators of gene expression act as master switches orchestrating both immune and neuronal processes. The long non-coding RNAs (lncRNAs) can regulate gene expression but when containing multiple miRNA-binding elements can serve as endogenous sponges neutralizing these miRNAs. Several chronic disorders reveal unique miRNA and lncRNA expression signatures, which recently generated big hopes for new perspectives for the development of diagnostic applications. ncRNAs modulating both neuronal and immune processes further promise therapeutic potential for diseases with a neuro-immune component [12,13]. Specifically, ncRNAs may regulate neuro-immune communication signals in the pain pathway by controlling macromolecular complexes in neurons, glia and immune cells. Understanding the concerted function of miRNA and lncRNAs in the regulation of nociceptive transduction and action potential generation, the synaptic transmission in the spinal dorsal horn and brain, the intercellular communication between neurons and non-neuronal cells, such as microglia, and the endogenous inhibitory control circuits, and defining their importance in the brain circuitries connected to cognitive, emotional and behavioural components involved in pain will shed new light on the so far enigmatic pathophysiology of neuropathic pain disorders. This review will focus on miRNAs and lncRNAs, as a large amount of literature suggests important and partially opposing roles for these ncRNAs in the establishment and chronification of neuropathic pain.

microRNA

Generation of miRNA

Pain conditions have been associated with deregulated miRNA expression from primary afferent nociceptors to brain areas associated with emotional components of pain perception [14–19]. Unique signatures of ncRNAs are associated with altered innate immune signalling and secreted miRNAs are even considered a new form of neuro-immune communication, and control immune cell activity as well as neuron function [13,20–22]. Thus, ncRNAs may act as essential modulators of processes for the establishment and maintenance of neuropathic pain.

Generation of mature miRNAs takes place within two distinct cellular compartments (Figure 1): In the nucleus, miRNAs are transcribed from DNA sequences by polymerase II as pri-microRNAs, processed by the RNAse-III enzyme Drosha and its auxiliary protein DGCR8 (Pasha) into 5′ capped and poly-adenylated pre-miRNAs, which can be several kilobases long, and may comprise one (monocistronic) or several (polycistronic) miRNA precursors [23]. Pre-miRNA sequences form characteristic hairpin loop structures of ∼70 nucleotides with a two-nucleotide overhang at the 3′ end and 3′ hydroxyl and 5′ phosphate groups [23–25]. Alternatively, short introns forming a hairpin-like structure called mirtrons can be spliced in a Drosha-independent manner to be further processed into a pre-miRNA [26]. These recently discovered features illustrate unexpected flexibility and highlight how alternative RNA processing can encode multiple functions by individual transcripts. Pre-miRNAs are shuttled from the nucleus into the cytosol by Exportin-5 transporter molecules where the RNase-III enzyme Dicer cleaves them towards biologically active mature duplex single-stranded miRNAs (∼18–25 nucleotides) [23]. Both single-stranded miRNAs derived from the 5´ arm (-5p) and 3´ arm (-3p) of the precursor can become integrated with Argonaute (Ago) proteins to form the RNA-Induced Silencing Complex (RISC, see Figure 1; [27]). Depending on the degree of homology, the miRNA induces translational repression (incomplete match) or target mRNA degradation (full match, not in mammals). More than 50% of mammalian miRNAs are located within host genes [28]. Especially those intragenic miRNAs exhibiting a high degree of conservation between species appear to be coordinately regulated and expressed with their host genes, either with synergistic or antagonistic correlation patterns [29,30]. For example, a number of interleukin-6 (IL-6) regulated miRNAs are up-regulated in rodent models of neuropathic pain and distinct functions have been described [31]. In contrast to intragenic miRNAs, the regulatory elements for extragenic miRNA are still largely enigmatic.

Classical and alternative mechanisms of mature miRNA generation and their action

Figure 1
Classical and alternative mechanisms of mature miRNA generation and their action

The microRNA gene is transcribed into a primary microRNA (pri-microRNA) or mirtron by polymerase II (Pol II). Drosha together with the accessory protein DGCR8 cleaves the pri-miRNA into a pre-miRNA. Alternatively, the pre-miRNA can arise from alternative splicing of the mirtron. Pre-miRNA binds to Exportin5 for nuclear export. Within the cytoplasm, Dicer and Argonaute 2 (AGO) cleave off the hairpin structure to generate a duplex miRNA. The two strands separate and within the RNA silencing complex (RISC) and in the presence of AGO the mature miRNA hybridizes with complementary seed sequences (8 nucleotides length) of possible target RNA strands (adapted from [32,33]). Depending on the degree of homology, the miRNA induces translational repression (incomplete match) or target mRNA degradation (full match, not in mammals) is induced.

Figure 1
Classical and alternative mechanisms of mature miRNA generation and their action

The microRNA gene is transcribed into a primary microRNA (pri-microRNA) or mirtron by polymerase II (Pol II). Drosha together with the accessory protein DGCR8 cleaves the pri-miRNA into a pre-miRNA. Alternatively, the pre-miRNA can arise from alternative splicing of the mirtron. Pre-miRNA binds to Exportin5 for nuclear export. Within the cytoplasm, Dicer and Argonaute 2 (AGO) cleave off the hairpin structure to generate a duplex miRNA. The two strands separate and within the RNA silencing complex (RISC) and in the presence of AGO the mature miRNA hybridizes with complementary seed sequences (8 nucleotides length) of possible target RNA strands (adapted from [32,33]). Depending on the degree of homology, the miRNA induces translational repression (incomplete match) or target mRNA degradation (full match, not in mammals) is induced.

Potential prospect of miRNA patterns emerging as possible signatures for pain disorders

miRNA in body fluids

In addition to their intracellular location and function, miRNAs are detectable in extracellular vesicles, such as exosomes, which are released, for example, by glia cells to cargo messages to other cell types in the central nervous system. Therefore, exosomes are anticipated to represent a specific mode of intercellular communication (for review see [34,35]). In addition, they are detectable in body fluids, such as cerebrospinal fluid (CSF), blood plasma or saliva, where they can be exploited for diagnostic purposes as so called ‘liquid biopsies’. Extracellular miRNAs are emerging as important communication units not only for mental disorders but also in the pain pathway offering the advantage of long distance messaging [36,37]. Several studies propose individual miRNAs or miRNA signatures for pathological pain disorders, such as CRPS, diabetic neuropathic pain or fibromyalgia. However, the assays available for these first studies assessing miRNAs in human body fluids cover only a small number of miRNAs and the marginal overlap for the same disease when assessed at different locations dampens the great hopes in the possible value of liquid biopsies for clinical use in pain diagnostics (see Table 1).

Table 1
Deregulated miRNAs identified in liquid biopsies of patients with pain disorders
DiseaseDetection methodSample type# up-regulated# down-regulatedmiRNA deregulated in minimum two studies on diseaseReference
CRPS qPCR array Blood 14 RNU48; miR-15a; miR-21; mir-25; miR-29c; miR-34a; mir-126; miR-212; mir-320B; miR-337; miR-367; miR-576; miR-645; mir-939; miR-1276; miR-1303 [38
CRPS qPCR array Serum-derived exosomes 62 70  [39
CRPS responders versus non-responders qPCR array Blood 32  [40
CRPS responders versus non-responders qPCR array Serum-derived exosomes  [41
Diabetic neuropathy qPCR array Serum 63 let-7d; let-7e; miR-28; miR-92a; miR-106a; miR-130a; miR-139; miR-150; mir-210; miR-342; miR-425; mir-486; miR-574 [42
Diabetic neuropathy with versus without critical limb ischaemia microarray Plasma  [43
Diabetic neuropathy with versus without critical limb ischaemia microarray Plasma  [44
Diabetic neuropathy qPCR array Serum 21  [45
DiseaseDetection methodSample type# up-regulated# down-regulatedmiRNA deregulated in minimum two studies on diseaseReference
CRPS qPCR array Blood 14 RNU48; miR-15a; miR-21; mir-25; miR-29c; miR-34a; mir-126; miR-212; mir-320B; miR-337; miR-367; miR-576; miR-645; mir-939; miR-1276; miR-1303 [38
CRPS qPCR array Serum-derived exosomes 62 70  [39
CRPS responders versus non-responders qPCR array Blood 32  [40
CRPS responders versus non-responders qPCR array Serum-derived exosomes  [41
Diabetic neuropathy qPCR array Serum 63 let-7d; let-7e; miR-28; miR-92a; miR-106a; miR-130a; miR-139; miR-150; mir-210; miR-342; miR-425; mir-486; miR-574 [42
Diabetic neuropathy with versus without critical limb ischaemia microarray Plasma  [43
Diabetic neuropathy with versus without critical limb ischaemia microarray Plasma  [44
Diabetic neuropathy qPCR array Serum 21  [45

In total, about 6000–7000 microRNA sequences have been identified, more than 2000 in humans [46]. In order to retrieve all known and possible currently unknown human miRNAs together with other ncRNAs and mRNAs, RNA sequencing (RNASeq) technologies represent the state of the art methodology for unbiased assessment of differentially expressed miRNA in patient and control cohorts [47,48]. For miRNA quantification in tissue, different experimental settings and also tissues, such as dorsal root ganglia (DRG), spinal cord or brain, require the use of appropriate reference genes and reliability is significantly higher if three different reference genes are used [49]. However, due to profound technical improvements, only unbiased RNASeq provides sufficient reliability and specificity for the discovery of disease specific miRNA patterns.

Nonetheless, for blood components, as well as nerve biopsies, a number of differentially regulated miRNAs has been identified and their target genes validated with a possible prospect to better understand disease pathophysiology (Table 2). Two up-regulated miRNAs (miR-124 and miR-155) target the histone deacetylase SIRT1, a structurally important promoter of axonal elongation, neurite outgrowth, and dendritic branching. SIRT1 also plays a role in memory formation by modulating synaptic plasticity and has protective roles in several neurodegenerative diseases [50]. The down-regulation of SIRT1 by miRNAs could thus be causally involved in neuropathic pain generation or in the exacerbation of the immune response [51]. Likewise, the increased IL-6 and VEGF expression resulting from decreased activity of miR-338-5p and miR-939, as well as miR-34a and miR-101 targeting Corticotropin releasing hormone receptor 1 (CRHR1) and Karyopherin beta 1 (KPNB1) are relevant candidates for the inflammatory component of neuropathic pain disorders [41,52,53].

Table 2
Deregulated miRNA in human samples including validated target genes
miRNARegulationTargetGene descriptionValidationPain disorderTissueReference
miR-124a ↑ SIRT1 Sirtuin 1 LucA Neuropathic pain patients CD4+ T cells [51
miR-132-3p ↑ GRIA1 Glutamate ionotropic receptor AMPA type subunit 1 LucA Neuropathic pain patients WBC / sural nerve [54
miR-155 ↑ SIRT1 Sirtuin 1 LucA Neuropathic pain patients CD4+ T cells [51
miR-199a-3p ↑ SERPINE2 Serpin family E member 2 LucA Diabetes type II Plasma [55
miR-455-3p ↑ TUBB3 Tubulin beta 3 class III mimic + immunofluorescence HIV-induced polyneuropathy Plasma [56
miR-34a ↓ XIST; YY1 X inactive specific transcript; YY1 transcription factor LucA CRPS Blood [57
miR-34a ↓ CRHR1 Corticotropin releasing hormone receptor 1 LucA CRPS Blood [53
miR-101 ↓ KPNB1 Karyopherin subunit beta 1 LucA Neuropathic pain patients Plasma / sural nerve [58
miR-338-5p ↓ IL6 Interleukin 6 LucA CRPS Plasma [41
miR-939 ↓ VEGFA Vascular endothelial growth factor A LucA CRPS Plasma [52
miRNARegulationTargetGene descriptionValidationPain disorderTissueReference
miR-124a ↑ SIRT1 Sirtuin 1 LucA Neuropathic pain patients CD4+ T cells [51
miR-132-3p ↑ GRIA1 Glutamate ionotropic receptor AMPA type subunit 1 LucA Neuropathic pain patients WBC / sural nerve [54
miR-155 ↑ SIRT1 Sirtuin 1 LucA Neuropathic pain patients CD4+ T cells [51
miR-199a-3p ↑ SERPINE2 Serpin family E member 2 LucA Diabetes type II Plasma [55
miR-455-3p ↑ TUBB3 Tubulin beta 3 class III mimic + immunofluorescence HIV-induced polyneuropathy Plasma [56
miR-34a ↓ XIST; YY1 X inactive specific transcript; YY1 transcription factor LucA CRPS Blood [57
miR-34a ↓ CRHR1 Corticotropin releasing hormone receptor 1 LucA CRPS Blood [53
miR-101 ↓ KPNB1 Karyopherin subunit beta 1 LucA Neuropathic pain patients Plasma / sural nerve [58
miR-338-5p ↓ IL6 Interleukin 6 LucA CRPS Plasma [41
miR-939 ↓ VEGFA Vascular endothelial growth factor A LucA CRPS Plasma [52

miRNA tissue expression in rodent models

Similar to human studies, differentially expressed miRNAs are extensively explored in preclinical neuropathic pain models [31,59–64]. In several of the routinely used models, specific miRNAs are up- or down-regulated all along the pain pathway and described in a number of recent publications and reviews [59,60,62,64–71]. The following section takes a more mechanistic approach and provides an overview of miRNAs deregulated in tissues in relevant preclinical pain models for which a relevant target gene and insight into neuropathic pain mechanisms have been validated (see Table 3).

Table 3
Look-up table of deregulated miRNA and target genes related to neuropathic human pain disorders or preclinical models of neuropathic pain. For ethical reasons, bilateral CCI was excluded as a model
miRNARegulationTargetGene descriptionValidationPain modelTissueSpeciesReference
miR‐15b ↑ Bace1 Beta-secretase 1 LucA Oxaliplatin‐induced peripheral neuropathy DRG Rat [72
miR-18a ↑ Kcna1; Kcnd3 Potassium voltage-gated channel subfamily A member 1; Potassium voltage-gated channel subfamily D member 3 LucA SNL DRG Rat [73
miR-19a ↑ Kcna4; Kcnc4; Kcnq5; Scn1b Potassium voltage-gated channel subfamily A member 4; Potassium voltage-gated channel subfamily C member 4; Potassium voltage-gated channel subfamily Q member 5; Sodium voltage-gated channel beta subunit 1 LucA SNL DRG Rat [73
miR-19b ↑ Kcna4; Kcnc4; Kcnq5; Scn1b Potassium voltage-gated channel subfamily A member 4; Potassium voltage-gated channel subfamily C member 4; Potassium voltage-gated channel subfamily Q member 5; Sodium voltage-gated channel beta subunit 1 LucA SNL DRG Rat [74
miR-32-5p ↑ Dusp5 Dual specificity phosphatase 5 LucA SNL Spinal cord / microglia Rat [75
miR-92a ↑ Kcnc4; Dpp10 Potassium voltage-gated channel subfamily C member 4; Dipeptidyl peptidase like 10 LucA SNL DRG Rat [73
miR-124a ↑ SIRT1 Sirtuin 1 LucA Neuropathic pain patients CD4+ T cells Human [51
miR-132-3p ↑ GRIA1 Glutamate ionotropic receptor AMPA type subunit 1 LucA Neuropathic pain patients WBC / sural nerve Human [54
miR-132-3p ↑ Gria1 Glutamate ionotropic receptor AMPA type subunit 1 LucA SNI Sural nerve / spinal cord / DRG Rat [54
miR-146a-5p ↑ Traf6 TNF receptor-associated factor 6 LucA SNL Spinal astrocytes Mouse [76
miR-155 ↑ Socs1 Suppressor of cytokine signalling 1 LucA CCI Spinal cord / microglia Rat [77
miR-155 ↑ SIRT1 Sirtuin 1 LucA Neuropathic pain patients CD4+ T cells Human [51
miR-183-5p ↑ Cldn1 Claudin 1 mimic + WB Perineural injection of sciatic nerve with recombinant tissue plasminogen activator Sciatic nerve Rat [78
miR-195 ↑ Ptch1 Patched 1 LucA Infraorbital nerve CCI Brain stem Rat [79
miR-195 ↑ Atg14 Autophagy related 14 LucA SNL Spinal cord / microglia Rat [80
miR-199a-3p ↑ SERPINE2 Serpin family E member 2 LucA Diabetes type II Plasma Human [55
miR-218 ↑ Socs3 Suppressor of cytokine signalling 3 LucA CCI Spinal cord / microglia Rat [81
miR-221 ↑ Socs1 Suppressor of cytokine signalling 1 LucA CCI Spinal cord / microglia Rat [82
miR-449a ↑ Pparg Peroxisome proliferator-activated receptor gamma LucA SCI Spinal cord Rat [83
miR-455-3p ↑ TUBB3 Tubulin beta 3 class III mimic + immunofluorescence HIV-induced polyneuropathy Plasma Human [56
miR-500 ↑ Gad1 Glutamate decarboxylase 1 LucA Paclitaxel-induced neuropathic pain Spinal dorsal horn Rat [84
miR-7a ↓ Scn2b Sodium voltage-gated channel beta subunit 2 LucA SNL DRG Rat [85
miR-7a ↓ Nefl Neurofilament light LucA SNL DRG Rat [86
miR-9 ↓ Foxp1 Forkhead box P1 mimic + WB Sciatic nerve crush DRG Mouse [87
miR-19a ↓ Mecp2 Methyl CpG binding protein 2 LucA SNI DRG Mouse [88
miR-20b-5p ↓ Akt3 AKT serine/threonine kinase 3 LucA CCI Spinal cord Rat [89
miR-21-5p ↓ Timp3; Ccl1 TIMP metallopeptidase inhibitor 3; C-C motif chemokine ligand 1 LucA CCI Spinal cord Rat [90
miR-23a-3p ↓ Cxcr4 Chemokine (C-X-C motif) receptor 4 LucA SNL Spinal cord Mouse [91
miR-23b ↓ Nox4 NADPH oxidase 4 LucA Traumatic SCI (neuropathic pain) Spinal cord Mouse [92
miR-26a-5p ↓ Mapk6 Mitogen-activated protein kinase 6 LucA CCI Spinal cord Rat [93
miR-30b ↓ Scn9a Sodium voltage-gated channel alpha subunit 9 LucA SNI DRG rat [94
miR-30b ↓ Scn3a Sodium voltage-gated channel alpha subunit 3 LucA SNL DRG Rat [95
miR-34a ↓ Scn2b; Vamp2 Sodium voltage-gated channel beta subunit 2; Vesicle-associated membrane protein 2 LucA CCI DRG Rat [96
miR-34a ↓ XIST; YY1 X inactive specific transcript; YY1 transcription factor LucA CRPS Blood Human [57
miR-34a ↓ CRHR1 Corticotropin releasing hormone receptor 1 LucA CRPS Blood Human [53
miR-34c ↓ Nlrp3 NLR family, pyrin domain containing 3 LucA CCI Spinal cord Mouse [97
miR-96 ↓ Scn3a Sodium voltage-gated channel alpha subunit 3 mimic + WB CCI DRG Rat [98
miR-101 ↓ KPNB1 Karyopherin subunit beta 1 LucA Neuropathic pain patients Plasma / sural nerve Human [58
miR-132 ↓ Mecp2 Methyl CpG binding protein 2 LucA SNI DRG Mouse [88
miR-141 ↓ Hmgb1 High mobility group box 1 LucA CCI DRG Rat [99
miR–142–3p ↓ Hmgb1 High mobility group box 1 LucA SNL DRG Mouse [100
miR-145 ↓ Akt3 AKT serine/threonine kinase 3 LucA CCI DRG Rat [101
miR-145 ↓ Rreb1 Ras responsive element binding protein 1 LucA CCI Spinal cord Rat [102
miR-182-5p ↓ Ephb1 Eph receptor B1 LucA CCI Spinal cord Mouse [103
miR-183 ↓ Mtor Mechanistic target of rapamycin kinase LucA CCI Spinal cord Rat [104
miR-183 ↓ Scn3a; Bdnf Sodium voltage-gated channel alpha subunit 3; Brain-derived neurotrophic factor mimic + qPCR SNL DRG Rat [105
miR-183-5p ↓ Kcnk2 Potassium two pore domain channel subfamily K member 2 (Trek1) LucA CCI DRG Rat [106
miR-186-5p ↓ Cxcl13 Chemokine (C-X-C motif) ligand 13 LucA SNL Spinal cord Mouse [107
miR-190a-5p ↓ Slc17a6 Solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6 (Vglut2) LucA Diabethic neuropathy Spinal cord Mouse [108
miR-200b ↓ Zeb1 Zinc finger E-box binding homeobox 1 LucA CCI Spinal cord / microglia Rat [109
miR-206 ↓ Bdnf Brain-derived neurotrophic factor LucA CCI DRG Rat [110
miR-206-3p ↓ Hdac4 Histone deacetylase 4 LucA CCI DRG Rat [111
miR-301 ↓ Mecp2 Methyl CpG binding protein 2 LucA SNI DRG Mouse [88
miR-338-5p ↓ IL6 Interleukin 6 LucA CRPS Plasma Human [41
miR-362-3p ↓ Pax2 Paired box 2 LucA SCI Spinal cord Rat [112
miR-429 ↓ Zeb1 Zinc finger E-box binding homeobox 1 LucA CCI Spinal cord/microglia Rat [109
miR–449a ↓ Trpa1; Kcnma1 Transient receptor potential cation channel, subfamily A, member 1; Potassium large conductance calcium-activated channel, subfamily M, alpha member 1 mimic + qPCR SNI DRG Mouse [113
miR-539 ↓ Grin2b Glutamate ionotropic receptor NMDA type subunit 2B mimic + WB CCI ACC Rat [114
miR-939 ↓ VEGFA Vascular endothelial growth factor A LucA CRPS Plasma Human [52
miRNARegulationTargetGene descriptionValidationPain modelTissueSpeciesReference
miR‐15b ↑ Bace1 Beta-secretase 1 LucA Oxaliplatin‐induced peripheral neuropathy DRG Rat [72
miR-18a ↑ Kcna1; Kcnd3 Potassium voltage-gated channel subfamily A member 1; Potassium voltage-gated channel subfamily D member 3 LucA SNL DRG Rat [73
miR-19a ↑ Kcna4; Kcnc4; Kcnq5; Scn1b Potassium voltage-gated channel subfamily A member 4; Potassium voltage-gated channel subfamily C member 4; Potassium voltage-gated channel subfamily Q member 5; Sodium voltage-gated channel beta subunit 1 LucA SNL DRG Rat [73
miR-19b ↑ Kcna4; Kcnc4; Kcnq5; Scn1b Potassium voltage-gated channel subfamily A member 4; Potassium voltage-gated channel subfamily C member 4; Potassium voltage-gated channel subfamily Q member 5; Sodium voltage-gated channel beta subunit 1 LucA SNL DRG Rat [74
miR-32-5p ↑ Dusp5 Dual specificity phosphatase 5 LucA SNL Spinal cord / microglia Rat [75
miR-92a ↑ Kcnc4; Dpp10 Potassium voltage-gated channel subfamily C member 4; Dipeptidyl peptidase like 10 LucA SNL DRG Rat [73
miR-124a ↑ SIRT1 Sirtuin 1 LucA Neuropathic pain patients CD4+ T cells Human [51
miR-132-3p ↑ GRIA1 Glutamate ionotropic receptor AMPA type subunit 1 LucA Neuropathic pain patients WBC / sural nerve Human [54
miR-132-3p ↑ Gria1 Glutamate ionotropic receptor AMPA type subunit 1 LucA SNI Sural nerve / spinal cord / DRG Rat [54
miR-146a-5p ↑ Traf6 TNF receptor-associated factor 6 LucA SNL Spinal astrocytes Mouse [76
miR-155 ↑ Socs1 Suppressor of cytokine signalling 1 LucA CCI Spinal cord / microglia Rat [77
miR-155 ↑ SIRT1 Sirtuin 1 LucA Neuropathic pain patients CD4+ T cells Human [51
miR-183-5p ↑ Cldn1 Claudin 1 mimic + WB Perineural injection of sciatic nerve with recombinant tissue plasminogen activator Sciatic nerve Rat [78
miR-195 ↑ Ptch1 Patched 1 LucA Infraorbital nerve CCI Brain stem Rat [79
miR-195 ↑ Atg14 Autophagy related 14 LucA SNL Spinal cord / microglia Rat [80
miR-199a-3p ↑ SERPINE2 Serpin family E member 2 LucA Diabetes type II Plasma Human [55
miR-218 ↑ Socs3 Suppressor of cytokine signalling 3 LucA CCI Spinal cord / microglia Rat [81
miR-221 ↑ Socs1 Suppressor of cytokine signalling 1 LucA CCI Spinal cord / microglia Rat [82
miR-449a ↑ Pparg Peroxisome proliferator-activated receptor gamma LucA SCI Spinal cord Rat [83
miR-455-3p ↑ TUBB3 Tubulin beta 3 class III mimic + immunofluorescence HIV-induced polyneuropathy Plasma Human [56
miR-500 ↑ Gad1 Glutamate decarboxylase 1 LucA Paclitaxel-induced neuropathic pain Spinal dorsal horn Rat [84
miR-7a ↓ Scn2b Sodium voltage-gated channel beta subunit 2 LucA SNL DRG Rat [85
miR-7a ↓ Nefl Neurofilament light LucA SNL DRG Rat [86
miR-9 ↓ Foxp1 Forkhead box P1 mimic + WB Sciatic nerve crush DRG Mouse [87
miR-19a ↓ Mecp2 Methyl CpG binding protein 2 LucA SNI DRG Mouse [88
miR-20b-5p ↓ Akt3 AKT serine/threonine kinase 3 LucA CCI Spinal cord Rat [89
miR-21-5p ↓ Timp3; Ccl1 TIMP metallopeptidase inhibitor 3; C-C motif chemokine ligand 1 LucA CCI Spinal cord Rat [90
miR-23a-3p ↓ Cxcr4 Chemokine (C-X-C motif) receptor 4 LucA SNL Spinal cord Mouse [91
miR-23b ↓ Nox4 NADPH oxidase 4 LucA Traumatic SCI (neuropathic pain) Spinal cord Mouse [92
miR-26a-5p ↓ Mapk6 Mitogen-activated protein kinase 6 LucA CCI Spinal cord Rat [93
miR-30b ↓ Scn9a Sodium voltage-gated channel alpha subunit 9 LucA SNI DRG rat [94
miR-30b ↓ Scn3a Sodium voltage-gated channel alpha subunit 3 LucA SNL DRG Rat [95
miR-34a ↓ Scn2b; Vamp2 Sodium voltage-gated channel beta subunit 2; Vesicle-associated membrane protein 2 LucA CCI DRG Rat [96
miR-34a ↓ XIST; YY1 X inactive specific transcript; YY1 transcription factor LucA CRPS Blood Human [57
miR-34a ↓ CRHR1 Corticotropin releasing hormone receptor 1 LucA CRPS Blood Human [53
miR-34c ↓ Nlrp3 NLR family, pyrin domain containing 3 LucA CCI Spinal cord Mouse [97
miR-96 ↓ Scn3a Sodium voltage-gated channel alpha subunit 3 mimic + WB CCI DRG Rat [98
miR-101 ↓ KPNB1 Karyopherin subunit beta 1 LucA Neuropathic pain patients Plasma / sural nerve Human [58
miR-132 ↓ Mecp2 Methyl CpG binding protein 2 LucA SNI DRG Mouse [88
miR-141 ↓ Hmgb1 High mobility group box 1 LucA CCI DRG Rat [99
miR–142–3p ↓ Hmgb1 High mobility group box 1 LucA SNL DRG Mouse [100
miR-145 ↓ Akt3 AKT serine/threonine kinase 3 LucA CCI DRG Rat [101
miR-145 ↓ Rreb1 Ras responsive element binding protein 1 LucA CCI Spinal cord Rat [102
miR-182-5p ↓ Ephb1 Eph receptor B1 LucA CCI Spinal cord Mouse [103
miR-183 ↓ Mtor Mechanistic target of rapamycin kinase LucA CCI Spinal cord Rat [104
miR-183 ↓ Scn3a; Bdnf Sodium voltage-gated channel alpha subunit 3; Brain-derived neurotrophic factor mimic + qPCR SNL DRG Rat [105
miR-183-5p ↓ Kcnk2 Potassium two pore domain channel subfamily K member 2 (Trek1) LucA CCI DRG Rat [106
miR-186-5p ↓ Cxcl13 Chemokine (C-X-C motif) ligand 13 LucA SNL Spinal cord Mouse [107
miR-190a-5p ↓ Slc17a6 Solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6 (Vglut2) LucA Diabethic neuropathy Spinal cord Mouse [108
miR-200b ↓ Zeb1 Zinc finger E-box binding homeobox 1 LucA CCI Spinal cord / microglia Rat [109
miR-206 ↓ Bdnf Brain-derived neurotrophic factor LucA CCI DRG Rat [110
miR-206-3p ↓ Hdac4 Histone deacetylase 4 LucA CCI DRG Rat [111
miR-301 ↓ Mecp2 Methyl CpG binding protein 2 LucA SNI DRG Mouse [88
miR-338-5p ↓ IL6 Interleukin 6 LucA CRPS Plasma Human [41
miR-362-3p ↓ Pax2 Paired box 2 LucA SCI Spinal cord Rat [112
miR-429 ↓ Zeb1 Zinc finger E-box binding homeobox 1 LucA CCI Spinal cord/microglia Rat [109
miR–449a ↓ Trpa1; Kcnma1 Transient receptor potential cation channel, subfamily A, member 1; Potassium large conductance calcium-activated channel, subfamily M, alpha member 1 mimic + qPCR SNI DRG Mouse [113
miR-539 ↓ Grin2b Glutamate ionotropic receptor NMDA type subunit 2B mimic + WB CCI ACC Rat [114
miR-939 ↓ VEGFA Vascular endothelial growth factor A LucA CRPS Plasma Human [52

Abbreviations: CCI, chronic constriction injury; CRPS, chronic regional pain syndrome; SCI, spinal cord injury; SNI, spared nerve injury; SNL, sciatic nerve ligation.

Mechanisms of miRNA action

Intracellular miRNAs suppress gene expression through tightly regulated steps within the microprocessor complex. For this, the miRNA within the ‘activated’ RNA-induced silencing complex (RISC) attaches to the 3′-untranslated region (UTR) of a given target mRNA primarily through its heptameric 5′ seed region (positions 2–8). One given mRNA harbouring one or several miRNA-binding sites in its 3′UTR can be regulated by various miRNAs. miRNA binding to the target gene’s miRNA recognition element (MRE) with full complementarity (which is rare in mammals) leads to destabilization and degradation (see also Figure 1); if the complementarity is incomplete, binding induces translational repression [115]. Protein expression may be down-regulated, although mRNA levels may remain unaltered in case of incomplete complementarity. miRNAs regularly target a multitude of target genes at the same time and thus may regulate entire signalling networks within one cell. In addition to their regulated target mRNAs, miRNAs hybridize with pseudogenes or circular RNAs (circRNAs) acting as endogenous miRNA neutralizing sponges, which inhibit or limit intracellular miRNA effects [116]. An unconventional role of extracellular miRNAs for rapid excitation of nociceptor neurons has been discovered recently: miRNA-let-7b induces rapid inward currents and excitation of nociceptors. These responses require the GUUGUGU motif, only occur in neurons co-expressing TLR7 and TRPA1, and are abolished in mice lacking Tlr7 or Trpa1. Thus, extracellular miRNAs may in addition to their regulatory function act as aptamers with a role as pain mediators via activating TLR7/TRPA1 in nociceptor neurons [117].

Since the first publication on analgesic miR-124 effects, miRNA regulation has attracted increasing attention in the pain field. However, the increasing number of reports raises the problem how expression patterns and mechanisms can be interpreted with a more global perspective. In order to warrant the highest degree of stringency, only miRNAs are addressed in this review based on publications validating miRNA expression together with direct regulation of target genes related to pain processing (Table 3).

miRNAs deregulated in the peripheral nerve

Only few studies address miRNAs in peripheral nerve tissue where axons, Schwann cells, connective tissue, cells of the vasculature and resident as well as transient immune cells can be possible sources (Figure 2). Up-regulation of miR-132-3p may target the ionotropic glutamate receptor AMPA type subunit 1 (Gria1) [54]. This has been identified as a microglial gene potentially linked to the maintenance of neuropathic pain [118]. Another up-regulated miRNA, miR-183-5p, targets Claudin 1, a tight junction protein that maintains the blood brain/blood nerve barrier and is down-regulated after nerve injury [78,119]. Along these lines, down-regulation of miR-101 by targeting Importin beta 1 (also known as Karyopherin beta 1, KPNB1) may release a brake on importin expression and augment the accessibility of axons to exosomal cargo as a mechanisms to foster nerve regeneration but possibly also for proalgesic factors [58,120].

Up- or down-regulated miRNAs in peripheral nerve or sensory ganglia and their target genes that are associated with neuropathic pain
Figure 2
Up- or down-regulated miRNAs in peripheral nerve or sensory ganglia and their target genes that are associated with neuropathic pain

Akt3: AKT serine/threonine kinase 3; Bace1: Beta-secretase 1; Bdnf: Brain-derived neurotrophic factor; Dpp10: Dipeptidyl peptidase like 10; Foxp1: Forkhead box P1; Hdac4: Histone deacetylase 4; Hmgb1: High mobility group box 1; Kcna1: Potassium voltage-gated channel subfamily A member 1; Kcna4: Potassium voltage-gated channel subfamily A member 4; Kcnd3: Potassium voltage-gated channel subfamily D member 3; Kcnk2: Potassium two pore domain channel subfamily K member 2 (Trek1); Kcnma1: Potassium large conductance calcium-activated channel, subfamily M, alpha member 1; Kcnc4: Potassium voltage-gated channel subfamily C member 4; Kcnq5: Potassium voltage-gated channel subfamily Q member 5; Mecp2: Methyl CpG binding protein 2; Nefl: Neurofilament light; Scn1b: Sodium voltage-gated channel beta subunit 1; Scn2b: Sodium voltage-gated channel beta subunit 2; Scn3a: Sodium voltage-gated channel alpha subunit 3; Scn9a: Sodium voltage-gated channel alpha subunit 9; Trpa1: Transient receptor potential cation channel, subfamily A, member 1; Vamp2: Vesicle-associated membrane protein 2. Scale bar: 100 µm (micrographs were kindly provided by M. Langeslag)

Figure 2
Up- or down-regulated miRNAs in peripheral nerve or sensory ganglia and their target genes that are associated with neuropathic pain

Akt3: AKT serine/threonine kinase 3; Bace1: Beta-secretase 1; Bdnf: Brain-derived neurotrophic factor; Dpp10: Dipeptidyl peptidase like 10; Foxp1: Forkhead box P1; Hdac4: Histone deacetylase 4; Hmgb1: High mobility group box 1; Kcna1: Potassium voltage-gated channel subfamily A member 1; Kcna4: Potassium voltage-gated channel subfamily A member 4; Kcnd3: Potassium voltage-gated channel subfamily D member 3; Kcnk2: Potassium two pore domain channel subfamily K member 2 (Trek1); Kcnma1: Potassium large conductance calcium-activated channel, subfamily M, alpha member 1; Kcnc4: Potassium voltage-gated channel subfamily C member 4; Kcnq5: Potassium voltage-gated channel subfamily Q member 5; Mecp2: Methyl CpG binding protein 2; Nefl: Neurofilament light; Scn1b: Sodium voltage-gated channel beta subunit 1; Scn2b: Sodium voltage-gated channel beta subunit 2; Scn3a: Sodium voltage-gated channel alpha subunit 3; Scn9a: Sodium voltage-gated channel alpha subunit 9; Trpa1: Transient receptor potential cation channel, subfamily A, member 1; Vamp2: Vesicle-associated membrane protein 2. Scale bar: 100 µm (micrographs were kindly provided by M. Langeslag)

miRNAs deregulated in the dorsal root and trigeminal ganglia

miRNA expression in the dorsal root or trigeminal ganglia (Figure 2 andTable 3) can be deregulated in various cell types, such as neurons, Schwann cells, resident or invading immune cells or even the vasculature. The most intensely studied sources are peptidergic and non-peptidergic primary afferent nociceptors. Conditional deletion of the miRNA-maturation enzyme Dicer exclusively in neurons expressing the nociceptor specific sodium channel Nav1.8 critically affects neuronal excitability [121] and increasing evidence suggests that several miRNAs directly or indirectly modulate neuron function (Table 3). Particular miRNAs are deregulated in peripheral neurons after nerve injury giving rise to deregulation of miRNA targeted ion channel and metabotropic receptor transcripts that presumably causes nociceptor dysfunction [117,121–123].

The most intensely investigated miRNA in the DRG is presently miR-21 that is expressed in neurons and up-regulated in several neuropathic pain models. Both intrathecal delivery of a miR-21-5p antagomir and conditional deletion of miR-21 in sensory neurons reduce neuropathic hypersensitivity [36]. As a new mechanism of action miR-21 cargo from neurons to immune cells via exosomes has been introduced recently: following capsaicin activation, miR-21-5p containing exosomes are released from cultured DRG and phagocytosed by macrophages in which the resulting increase in miR-21-5p levels promotes a pro-inflammatory phenotype. Both up-regulation and release of miR-21 contribute to sensory neuron-macrophage communication after damage to the peripheral nerve [36]. Since intrathecal miR-21 injection induces pain hypersensitivity in wild-type mice but not in mice with a global deletion of toll-like receptor 8 (Tlr8−/−), the TLR8 receptor appears to act as a downstream effector of miR-21 to maintain neuropathic pain; however, a direct targeting of the Tlr8 gene has not been validated yet [124].

miR-18, miR-19a, miR-19b as well as mir-92 are also up-regulated in neuropathic pain models and in turn down-regulate potassium channels including Kcna1, Kcna4, Kcnc4, Kcnd3 and Kcnq5 [73]. The suppression of potassium channels in general increases neuronal excitability and this may be a relevant mechanism causing nociceptor excitation and sensitization [125,126]. In line with the alterations towards hyperexcitability, several down-regulated miRNAs targeting voltage-gated sodium channels may further promote neuronal excitability by releasing the breaks on sodium channel expression: two alpha subunits of voltage-gated sodium channels, Scn3a giving rise to Nav1.3 and Scn9a giving rise to pain-related Nav1.7, are targeted by the down-regulated miRNAs miR-30b, miR-96 and miR-183, which probably contributes to up-regulation of the ion channel alpha subunits in neuropathic pain models [94,95,98,105]. In addition, down-regulated miR-7a and miR-34a targeting sodium voltage-gated channel beta subunit 2 (Scn2b) may be involved in improved trafficking of already formed alpha subunits [85,96]. Furthermore, transducer channels, such as TRPA1, can occur as a consequence of miR–449a down-regulation [113]. The only potential change counteracting these proalgesic alterations refers to the down-regulated miR-183-5p that targets potassium channel Trek1, a two pore domain potassium channel subfamily member 2 (Kcnk2), which as a leak current keeps the membrane potential hyperpolarized [106]. The up-regulation of this channel may counteract the brake set on potassium channel expression by the miR-17-92 cluster.

Alterations in enzymatic activity, inflammatory signalling pathways and epigenetic regulators are amongst the mechanisms targeted by deregulated miRNAs in DRG. For example, miR-15b up-regulation targets Beta-secretase 1 that may be involved in neuroprotective processes, whereas miR-145 down-regulation appears to release the break on Akt3 that can be targeted by miR-15a or miR-20b-5p mimics to relieve neuropathic pain [72,89,101,127]. Down-regulation of miR-183 and miR-206 contributes to the up-regulation of brain-derived neurotrophic factor (Bdnf) that is required for regenerative processes but also is an important pain modulator [105,110,128,129] (for review see [130]). Finally, several down-regulated miRNAs (miR-19a, miR-132, miR-301) appear to affect epigenetic regulatory pathways, such as Mecp2 or HDAC4 (via miR-206-3p), and dependent processes that are relevant contributors fueling pathological functions in the spinal dorsal horn but may also be relevant for dysfunction of primary afferent nociceptors [88,111,131–135].

miRNAs deregulated in the spinal cord

miR-124 was the first miRNA for which an analgesic action at spinal cord level was demonstrated and correlated with a shift in the M1/M2 microglial marker ratio towards an anti-inflammatory phenotype [136]. The functional consequences of miR-103 regulation of Cav1.2 calcium channels and intrinsic excitability of spinal projection neurons have also been demonstrated [123]. More evidence supporting miRNA analgesic effects emerge from mice intrathecally receiving miR-124 or miR-103, which are reported to prevent and treat persistent inflammatory and neuropathic pain [123,136]. Despite the fact that these miRNA treatments reduce signatures of synaptic modification, neuroinflammation and microglial response, the full extent and the mechanisms of the analgesic effect are not fully understood to date [34,123,136,137]. However, several miRNAs have been found deregulated in rodent pain models together, mainly in microglia, with validated downstream targets with a potential relevance to pain signalling (Figure 3).

Deregulated miRNA in spinal cord and brain with the respective associated target genes
Figure 3
Deregulated miRNA in spinal cord and brain with the respective associated target genes

Although specific brain areas are involved in different aspects of processing pain perception, miRNA expression so far has not been addressed specifically within these areas under neuropathic pain conditions. Akt3: AKT serine/threonine kinase 3; Atg14: Autophagy related 14; Dusp5: Dual specificity phosphatase; Ccl1: C-C motif chemokine ligand 1; Cxcl13: Chemokine (C-X-C motif) ligand 13; Cxcr4: Chemokine (C-X-C motif) receptor 4; Ephb1: Eph receptor B1; Gad1: Glutamate decarboxylase 1; Grin2b: Glutamate ionotropic receptor NMDA type subunit 2B; Mapk6: Mitogen-activated protein kinase 6; Mtor: Mechanistic target of rapamycin kinase; Nlrp3: NLR family, pyrin domain containing 3; Nox4: NADPH oxidase 4; Pax2: Paired box 2; Pparg: Peroxisome proliferator-activated receptor gamma; Ptch1: Patched 1; Rreb1: Ras responsive element binding protein 1; Slc17a6: Solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter); Socs1: Suppressor of cytokine signalling 1; Socs3: Suppressor of cytokine signalling 3; Timp3: TIMP metallopeptidase inhibitor 3; Traf6: TNF receptor-associated factor 6; Zeb1: Zinc finger E-box binding homeobox 1

Figure 3
Deregulated miRNA in spinal cord and brain with the respective associated target genes

Although specific brain areas are involved in different aspects of processing pain perception, miRNA expression so far has not been addressed specifically within these areas under neuropathic pain conditions. Akt3: AKT serine/threonine kinase 3; Atg14: Autophagy related 14; Dusp5: Dual specificity phosphatase; Ccl1: C-C motif chemokine ligand 1; Cxcl13: Chemokine (C-X-C motif) ligand 13; Cxcr4: Chemokine (C-X-C motif) receptor 4; Ephb1: Eph receptor B1; Gad1: Glutamate decarboxylase 1; Grin2b: Glutamate ionotropic receptor NMDA type subunit 2B; Mapk6: Mitogen-activated protein kinase 6; Mtor: Mechanistic target of rapamycin kinase; Nlrp3: NLR family, pyrin domain containing 3; Nox4: NADPH oxidase 4; Pax2: Paired box 2; Pparg: Peroxisome proliferator-activated receptor gamma; Ptch1: Patched 1; Rreb1: Ras responsive element binding protein 1; Slc17a6: Solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter); Socs1: Suppressor of cytokine signalling 1; Socs3: Suppressor of cytokine signalling 3; Timp3: TIMP metallopeptidase inhibitor 3; Traf6: TNF receptor-associated factor 6; Zeb1: Zinc finger E-box binding homeobox 1

Deregulated miRNAs in the spinal cord (Figure 3) can emerge from various sources, such as neurons, microglia, astroglia or even the vasculature. The most intensely investigated sources are microglia that react to maintained nociceptive input to the spinal cord with proliferation and a change in phenotype and activity (microgliosis). In microglia, a number of up-regulated miRNA (miR-155, miR-218 and miR-221) can inhibit the expression of suppressors of cytokine signalling, such as Socs1, and may promote inflammatory signatures, such as microgliosis [77,81,82]. A novel regulator of microglia, Dual specificity phosphatase 5 (Dusp5) is regulated by miR-32-5p, and this is involved in the regulation of neuroinflammatory processes, such as cytokine release in the spinal cord [75].

At the same time several miRNAs, such as miR-200b and miR-429, are down-regulated in microglia after nerve injury, and Zeb1 (Zinc finger E-box binding homeobox 1) has been identified as a target of these two miRNAs [109]. Zeb family members are essential for the developing nociceptors in the DRG [138]. ZEB1 overexpression regulates the microglia response after ischemic stroke and in turn inhibits the production of astrocytic CXCL1 which leads to a decline in neutrophil infiltration, thereby reducing CNS inflammation. This suggests involvement of miR-200b and miR-429 suppression in the resolution of neurological injury [139]. In contrast, miR-21-5p targeting the chemokine Ccl1 [90], miR-23a-3p targeting Cxcr4 [91], miR-34 targeting Nlrp3 (NLR family, pyrin domain containing 3) [97], and miR-186-5p targeting Cxcl13 [107] are down-regulated leading to increased expression of inflammatory mediators and an augmentation of inflammatory processes in the spinal cord. Other down-regulated miRNAs (miR-145, miR-183) at the same time may release the suppression of key components affecting cell morphology and microglia function via transcription factor Rreb1 [102,140] or mTOR [104,141] together with miR-195 up-regulation, which suppresses Autophagy related 14 (Atg14 [80]). These microRNAs appear to orchestrate spinal neuroinflammation related to neuropathic pain. Another negative-feedback regulator of the astrocyte-mediated inflammatory response to injury is miR-146a, which is up-regulated in astrocytes following nerve injury, and targets TNF receptor-associated factor 6 (Traf6) [76,142]. Persistent up-regulation of Traf6 in spinal cord astrocytes in the late phase after nerve injury maintains neuropathic pain by integrating TNF-α and IL-1β signaling and activating the JNK/CCL2 pathway and increased miR-146a expression can set a brake to the neuroinflammatory component maintained by Traf6 [76,143].

In addition, miRNAs are generated and act within neurons, and there are several possible mechanisms for activity-dependent miRNA regulation. First, upon strong synaptic input, Ca2+ influx through NMDA receptors activates the Ca2+-dependent enzyme calpain that can liberate Dicer from postsynaptic densities and stimulate Dicer RNAse III activity to facilitate processing of pre-miRNAs into mature miRNAs (Figure 4) [144]. Second, increased intracellular Ca2+ can induce de novo miRNA transcription. Third, although less is known about the mechanism of miRNA degradation, another possible mechanism controlling mature miRNA expression may be the activity-dependent degradation of the RISC component MOV10 by the proteasome. However, it is still not sufficiently clear whether MOV10 degradation promotes the disassembly of RISC and thus augments the turnover of miRNAs (for review see [145]).

Activity dependent generation of miRNA in neurons affecting synapse specific protein synthesis
Figure 4
Activity dependent generation of miRNA in neurons affecting synapse specific protein synthesis

Adapted from [145].

Figure 4
Activity dependent generation of miRNA in neurons affecting synapse specific protein synthesis

Adapted from [145].

Of particular interest and importance in the spinal dorsal horn (SDH) are up-regulated miRNAs targeting inhibitory ion channels, such as GABA or K+ channels. In the chronic constriction injury (CCI) model, miR-182-5p is down-regulated and targets Ephb1 [103]. This is of particular interest, since ephrinB–EphB receptor signalling plays a critical role in induction and maintenance of neuropathic pain by regulating neural excitability and synaptic plasticity in the DRG and the SDH [146]. Up-regulation of miR-449a via targeting peroxisome proliferator-activated receptor gamma (Pparg) and reduced Pparg expression can aggravate the increased neuroexcitability and neuroexcitotoxicity associated with neuropathic pain [83,147]. Increased excitatory activity in SDH may be further fueled by the release of glutamate transporter vGluT2 (Slc17a6, Solute carrier family 17 member 6) expression and augmentation by down-regulated miR-190a-5p [108,148–150]. At the same time, glutamate decarboxylase 1 (Gad1) regulates GABA synthesis and transport [151], and reduced expression of Gad1 impairs the function of GABAergic synapses, which appears to be induced by up-regulation of miR-500 [84]. The transcription factor Paired box 2 (Pax2) is necessary for the GABAergic differentiation [151] and a loss of SDH GABAergic interneurons causes reduced GABAergic tone that contributes to neuropathic pain [152]. Therefore, the down-regulation of miR-362-3p targeting Pax2 may rather be a compensatory change to restore GABAergic signaling in the SDH [112]. These processes are further enhanced by the down-regulation of three miRNAs (miR-20b-5p, miR-23 and miR-26a-5p) leading to the increased expression of the kinases Akt3, Nox4 and Mapk6 whose relevance for neuropathic pain is well accepted [89,92,93]. Together, miRNAs are emerging as major controllers of neuro-immune processes in the SDH by switching neurons as well as non-neuronal cells into proalgesic modes of action and promoting the development and maintenance of signatures aggravating neuropathic pain at spinal cord level.

miRNAs deregulated in the brain

miRNAs act at the neuro-immune interface which controls neuronal plasticity and memory but also are linked to the etiology of anxiety and mood disorders [12,13,34]. Deficits in the interaction of immune cells and neurons together with cognitive and emotional alterations in patients with neuropathic or neurogenic pain syndromes are hypothesized to converge on ncRNA deregulated mechanisms along the entire neuraxis, and alterations in ncRNAs expression may account for the variation of susceptibility to certain types of pain or even for the responsiveness to analgesics and development of opioid tolerance [153].

As in the spinal cord, neuronal and non-neuronal cells contribute to potential disease specific miRNA patterns in brain regions that are relevant for the processing of painful stimuli. Brain specific miRNAs are emerging as regulators of cognition, neuronal plasticity and memory, affecting synapse structure and function, and specific miRNAs not only control cognition and emotional processes but also neuro-immune communication in the brain [13,154]. In general, happiness, anxiety and depression seem to depend on miRNA expression levels, and specific miRNAs are deregulated in depression, anxiety, and preclinical models of psychological stress. Moreover psychoactive agents including antidepressants and mood stabilizers utilize miRNAs as downstream effectors [12]. In the brain, AMPA-mediated synaptic transmission is reduced by neuronal over-expression of miR-125b and increased by miR-132 due to differential regulation of glutamate NR2A and NR2B receptor mRNA [155]. Other glutamate receptor subunits in the brain are regulated by dopamine through miR-181a, which has been associated with the pain system [156]. In particular, miR-132 is a highly interesting brain specific miRNA, since it is up-regulated by BDNF and other growth factors in cortical neurons resulting in an increased expression of synaptic glutamate receptors NR2A, NR2B and AMPA GluR1 [157,158]. In the hippocampus, miR-132 targets acetylcholinesterase and this is relevant for stress-induced cognitive deficits. In the amygdala miR-34 is associated with the repression of stress-induced anxiety [159,160]. In neuropathic pain, maladaptive responses of the nucleus accumbens have been associated with deregulated miRNAs [66]. Endogenous pain control systems including GABAergic and opioidergic synaptic signals are down-regulated by miRNAs, such as miR-134 or miR-181a, with some of them linking miRNAs like let-7 or miR-339 to opioid tolerance [161–164]. Despite the increasing number of reports, only few studies validate the deregulated miRNAs acting on specific target genes in the brain in neuropathic pain models (Figure 3). Down-regulation of miR-539 can release the brake on the expression of Grin2b (Glutamate ionotropic receptor NMDA type subunit 2B) and enhance the formation of pain memory in the anterior cingulate cortex [114] and also in the brain stem, up-regulation of miR-195 and its target gene patched 1 (Ptch1) has been reported [79]. Altogether, although relevant roles for miRNA regulated processes in the pathogenesis of neuropathic pain can be anticipated also for relevant brain areas this field of pain research is still in its infancy.

Long ncRNAs

Synthesis and function

Long ncRNAs (lncRNAs) of more than 200 nucleotides are the second most studied group of ncRNAs. Currently 172,216 human and 131,697 mouse transcripts are annotated in the systematic database NONCODEv5 [165], whereas the curated knowledgebase LncBook documents 270,044 human lncRNAs [166]. Depending on their genomic location, lncRNA sequences can be intronic, natural antisense transcripts (NATs), sense, extragenic, enhancer, promoter and bidirectional, and can have a linear or circular structure (circRNAs [167,168]). lncRNA expression patterns highly depend on cell and tissue type as well as on developmental or disease states [169]. In general, lncRNA genes resemble protein coding genes, as their transcription follows similar rules [169,170]. lncRNAs can be capped at their 5′ end, polyadenylated at their 3′ end, alternatively adenylated or not, and can undergo alternative splicing [167,171]. Besides similar transcriptional mechanisms to protein coding genes, lncRNA biogenesis processes can include cleavage by ribonuclease P to form triple helical structures and the formation of circular structures [168]. Their localization in the nucleus, cytoplasm, mitochondria, ribosomes, extracellular membranes and exosomes defines and controls their functions in cellular processes, such as transcriptional, post-transcriptional and epigenetic regulation [169,170,172]. lncRNAs can act as decoys, competing endogenous RNAs (ceRNAs), guides, scaffolds and signals [167,168,173]. In the nucleus, lncRNAs can affect transcription via epigenetic mechanisms and chromatin remodeling as well as by stabilizing mRNA and changing mRNA splicing [173]. As decoys, lncRNAs can bind to proteins, such as transcription factors or RNA-binding proteins, making them unavailable to perform their actions, which can result in transcriptional inhibition and mRNA degradation [167]. Furthermore, lncRNAs can act as competing endogenous RNA (ceRNA) sponging miRNAs and making them unavailable for interaction with their target genes. In contrast to miRNAs, lncRNAs interact with single targets to up- or down-regulate expression levels. Due to the various mechanisms of actions and the high number of lncRNAs, their precise functions and interconnections are not fully unveiled. Their implications in pain conditions have been addressed mostly in animal models, providing a firm indication on the importance of lncRNAs and circRNAs in the establishment and development of pain; however, the precise mechanisms are not fully elucidated.

lncRNAs as possible signatures for pain disorders

lncRNAs are deregulated in diabetic peripheral neuropathy and CRPS [57,137,174–176], and similar to miRNAs, they can be detected in liquid biopsies (Table 4). The most studied lncRNA in DNP is NONRATT021972 which is up-regulated in the serum and correlates with higher neuropathic pain scores, indicating its potential as a biomarker [137,177]. Another up-regulated ncRNA in Type 2 diabetes mellitus and DNP serum is uc.48+ that is involved in purinergic receptor-mediated responses [74,178]. Amongst 1327 deregulated lncRNAs in the PBMCs of female patients with DNP, MALAT1, H19, PVT1 and MIR143HG could potentially qualify as biomarkers [174]. In female CRPS patients, XIST appears as a promising indicator of poor responsiveness to ketamine [57]. XIST acts as a ceRNA on miR-34a, thus enhancing expression levels of the transcription factor YY1 promoting XIST expression in an autoregulatory loop [57]. CircRNAs are much less studied in patients with neuropathic pain and currently there is only one study showing that circHIPK3 expression positively correlates with the severity of neuropathic pain in diabetic patients [176].

Table 4
Deregulated lncRNAs identified in liquid biopsies of patients with pain disorders
DiseaseDetection methodSample typeUp-regulationDown-regulationDeregulated lncRNA or circRNAReference
Diabetic neuropathy microarray PBMCs 256 1071 MALAT1, H19, PVT1, MIR143HG [174
Diabetic neuropathy RT-qPCR Serum na NONRATT021972 [137
Diabetic neuropathy RT-qPCR Serum na NONRATT021972 [177
Diabetic neuropathy RT-qPCR Serum na uc.48+ [179
Diabetic neuropathy RT-qPCR Serum na uc.48+ [178
Diabetic neuropathy RT-qPCR Serum na circHIPK3 [176
CRPS in female patients RT-qPCR Whole blood na XIST [57
DiseaseDetection methodSample typeUp-regulationDown-regulationDeregulated lncRNA or circRNAReference
Diabetic neuropathy microarray PBMCs 256 1071 MALAT1, H19, PVT1, MIR143HG [174
Diabetic neuropathy RT-qPCR Serum na NONRATT021972 [137
Diabetic neuropathy RT-qPCR Serum na NONRATT021972 [177
Diabetic neuropathy RT-qPCR Serum na uc.48+ [179
Diabetic neuropathy RT-qPCR Serum na uc.48+ [178
Diabetic neuropathy RT-qPCR Serum na circHIPK3 [176
CRPS in female patients RT-qPCR Whole blood na XIST [57

lncRNA tissue expression in animal models

lncRNAs and circRNAs are differentially expressed in animal pain models in sciatic nerve, DRG and spinal cord [180–185]. Most of these studies combine lncRNA and mRNA expression analyses including complex bioinformatics to generate networks of potential functional interactions [180,186,187]; however, only few have been explored using a more mechanistic approach (Table 5). Differential expression of lncRNAs upon peripheral nerve injuries is time-dependent and varies between strains and species [182,183,185]. LncRNAs play important roles in neuropathic pain processes not only in neurons, but also in non-neuronal cells, such as Schwann cells, satellite glial cells, macrophages and microglia [74,83,185,188–191].

Table 5
Deregulated lncRNA and target genes related to neuropathic human pain disorders or preclinical models of neuropathic pain. For ethical reasons, bilateral CCI was excluded as a model
lncRNARegulationTargetGene descriptionValidationPain modelTissueSpeciesMechanismReference
Competing endogenous RNA 
TUSC7 ↓ miR-449a microRNA 449a RIP SCI Spinal cord Rat lncRNA–miRNA interaction [83
XIST ↑ miR-34a microRNA 34a LucA CRPS; CFA-induced inflammation Whole blood Human; mouse lncRNA–miRNA interaction [57
circHIPK3 ↑ miR-124 microRNA 124 LucA/RNA pull down DNP Serum; DRG Human;rat lncRNA–miRNA interaction [176
Upregulation of target gene 
BC168687 ↑ Trpv1 Transient receptor potential vanilloid type 1 siRNA/WB, immunostaining DPN DRG Rat Not specified [192
BC168687 ↑ P2rx7 Purinergic receptor P2X 7 siRNA/RT-qPCR, WB, immunostaining DNP Satellite glial cells cultures Rat Not specified [191
BC168687 ↑ P2rx7 Purinergic receptor P2X 7 siRNA/WB, immunostaining DPN DRG Rat Not specified [193
MRAK009713 ↑ P2rx3 Purinergic receptor P2X 3 siRNA/WB, RIP, immunostaining CCI DRG Rat lncRNA–protein interaction [194
NONRATT021972 ↑ P2rx3 Purinergic receptor P2X 3 siRNA/WB, immunostaining DPN DRG Rat Not specified [177
NONRATT021972 ↑ P2rx7 Purinergic receptor P2X 7 siRNA/WB, immunostaining DPN DRG Rat lncRNA–mRNA prediction [195
PKIA-AS1 ↑ CDK6 Cyclin dependent kinase 6 LucA; siRNA/WB; RIP SNL Spinal cord Rat Enhancement of promotor activity [196
uc.48+ ↑ P2rx3 Purinergic receptor P2X 3 siRNA/WB, immunostaining DPN DRG Rat Not specified [178
uc.48+ ↑ P2rx7 Purinergic receptor P2X 7 siRNA/WB, immunostaining; RIP CCI-ION Trigeminal ganglia Rat lncRNA–protein interaction [197
Down-regulation of target gene 
Kcna2-NAT ↑ Kcna2 Potassium voltage-gated channel subfamily A member 2 LucA; overexpression, WB SNL, CCI, sciatic nerve axotomy DRG Rat lncRNA–mRNA interaction [198
Egr2-NAT ↑ Egr2 Early growth response 2 Overexpression; anti-GapMers; ChIP/WB; RIP/WB Sciatic nerve injury DRG: sciatic nerve Mouse Chromatin remodelling complex recruitment [199
lncRNARegulationTargetGene descriptionValidationPain modelTissueSpeciesMechanismReference
Competing endogenous RNA 
TUSC7 ↓ miR-449a microRNA 449a RIP SCI Spinal cord Rat lncRNA–miRNA interaction [83
XIST ↑ miR-34a microRNA 34a LucA CRPS; CFA-induced inflammation Whole blood Human; mouse lncRNA–miRNA interaction [57
circHIPK3 ↑ miR-124 microRNA 124 LucA/RNA pull down DNP Serum; DRG Human;rat lncRNA–miRNA interaction [176
Upregulation of target gene 
BC168687 ↑ Trpv1 Transient receptor potential vanilloid type 1 siRNA/WB, immunostaining DPN DRG Rat Not specified [192
BC168687 ↑ P2rx7 Purinergic receptor P2X 7 siRNA/RT-qPCR, WB, immunostaining DNP Satellite glial cells cultures Rat Not specified [191
BC168687 ↑ P2rx7 Purinergic receptor P2X 7 siRNA/WB, immunostaining DPN DRG Rat Not specified [193
MRAK009713 ↑ P2rx3 Purinergic receptor P2X 3 siRNA/WB, RIP, immunostaining CCI DRG Rat lncRNA–protein interaction [194
NONRATT021972 ↑ P2rx3 Purinergic receptor P2X 3 siRNA/WB, immunostaining DPN DRG Rat Not specified [177
NONRATT021972 ↑ P2rx7 Purinergic receptor P2X 7 siRNA/WB, immunostaining DPN DRG Rat lncRNA–mRNA prediction [195
PKIA-AS1 ↑ CDK6 Cyclin dependent kinase 6 LucA; siRNA/WB; RIP SNL Spinal cord Rat Enhancement of promotor activity [196
uc.48+ ↑ P2rx3 Purinergic receptor P2X 3 siRNA/WB, immunostaining DPN DRG Rat Not specified [178
uc.48+ ↑ P2rx7 Purinergic receptor P2X 7 siRNA/WB, immunostaining; RIP CCI-ION Trigeminal ganglia Rat lncRNA–protein interaction [197
Down-regulation of target gene 
Kcna2-NAT ↑ Kcna2 Potassium voltage-gated channel subfamily A member 2 LucA; overexpression, WB SNL, CCI, sciatic nerve axotomy DRG Rat lncRNA–mRNA interaction [198
Egr2-NAT ↑ Egr2 Early growth response 2 Overexpression; anti-GapMers; ChIP/WB; RIP/WB Sciatic nerve injury DRG: sciatic nerve Mouse Chromatin remodelling complex recruitment [199

Abbreviations: CCI, chronic constriction injury; CCI-ION, chronic constriction injury of the infraorbital nerve; CFA, Complete Freund’s adjuvant; CRPS, chronic regional pain syndrome; DPN, diabetic peripheral neuropathy; DRG, dorsal root ganglia; LucA, luciferase assay; RIP, RNA immunoprecipitation; SCI, spinal cord injury; SNL, sciatic nerve ligation; WB, Western blot.

lncRNAs deregulated in the peripheral nerve

Differential expression of lncRNAs and circRNAs in peripheral nerves in neuropathic pain models have not been addressed in detail. Deregulated lncRNAs are reported in the sciatic nerve after a sciatic nerve crush [185]. This model is used to explore nerve regeneration and numerous differentially expressed lncRNAs were associated with inflammatory and immune responses, which could possibly be relevant for neuropathic pain [185]. Particularly, NONMMUG014387 enhances the proliferation of cultured mouse Schwann cells, presumably via cis-upregulation of collagene triple helix repeat containing 1 (Cthrc1) [185], whereas the antisense to the Egr2 promoter ncRNA (Egr2-antisense-RNA) down-regulates Egr2 and promotes demyelination upon peripheral nerve injury by an epigenetic mechanism, in which a chromatin remodeling complex is assembled at the Egr2 promoter [199].

lncRNAs deregulated in the dorsal root and trigeminal ganglia

Differentially expressed lncRNAs and their functions are intensely studied in rodent neuropathic pain models, whereas circRNAs have not been addressed yet [200,201]. lncRNAs down-regulate voltage-gated channels and one of the first lncRNAs found to be implicated in pain is the endogenous voltage-gated potassium channel (Kv) Kcna2-antisense-RNA (NAT), which upon nerve injury is transcriptionally induced by myeloid zinc finger protein 1 (MZF1) and specifically targets and down-regulates Kcna2, resulting in reduced potassium currents and increased DRG excitability [202]. Other up-regulated lncRNAs, such as BC168687 [192,193], MRAK009713 [194], NONRATT021972 [177,178,195] and uc.48+ [178,179], contribute to mechanical hypersensitivity via cell-type specific interactions and induction of different purinergic receptors known for their pain modulating properties. For example, NONRATT021972 and uc.48+ up-regulate the ionotropic purinoreceptor P2X3 in small-medium DRG neurons but P2X7 in satellite glia cells [177–179,195]. BC168687 up-regulates TRPV1 and MRAK009713 promotes the up-regulation of P2X3 receptor in DRG neurons [192,194]. Additionally, uc.48+ inhibition alleviates mechanical hypersensitivity in a rat model for trigeminal neuralgia, by inhibiting the expression of P2X7 receptor in glial cells within the trigeminal ganglia [203]. In addition, uc.48+ appears to exert inhibitory effects on neuroregeneration since inhibition of uc.127 enhances the outgrowth of DRG neurons in vitro [204].

lncRNAs deregulated in the spinal cord and brain

Most of the studies focus on whole spinal cord tissues and therefore do not distinguish between alterations occurring in neuronal and non-neuronal cells [183,184,205–208]. Nevertheless, the identification of deregulated lncRNAs and circRNAs and the computational construction of interaction-networks between lncRNAs/circRNAs–miRNAs–mRNAs provide directions for future studies and potential therapeutic targets. Interestingly, not only SNI-induced mechanical hyperalgesia but also the differential expression of lncRNAs is alleviated by the tetracycline antibiotic minocycline [205]. Few lncRNAs have been functionally investigated at the spinal cord level. PK1A-AS1 overexpression enhances pain behaviors by demethylating the promoter region and promoting the expression of CDK6, an important component in neuroinflammation and neuropathic pain, whereas PK1A-AS1 down-regulation exerts analgesic effects [196]. Of the lncRNAs that are down-regulated after peripheral nerve injury, TUSC7 may be of particular mechanistic relevance, as its up-regulation inhibits the activation of microglia by targeting miR-449a and increasing the expression of the miR-499a target gene PPAR-γ [83]. The only circRNA that has been functionally related to DPN is circHIPK3 which is up-regulated in diabetic rats, acts as a miR-124 sponge and inhibition of circHIPK3 has analgesic and anti-inflammatory effects [176]. In contrast with the emerging role of lncRNAs in the spinal cord, their importance in pain processing brain areas has so far not been mechanistically addressed.

Synopsis

The field of ncRNAs is quickly expanding in the recent years and numerous studies have addressed and associated differentially expressed ncRNAs with neuropathic pain disorders in humans and their corresponding preclinical models. Against initial expectations, common miRNA candidates indicative of neuropathic pain in liquid biopsies have not emerged so far but lncRNAs may offer better perspectives. Whereas the suitability of miRNAs as clinically applicable biomarkers for pain disorders is still disputable, numerous studies have provided novel mechanistic insight into the role of miRNAs in the molecular sequelae involved in the pathogenesis of neuropathic pain along the entire pain pathway. Specific processes within neurons, immune cells, glia as the cellular components of the neuropathic pain triad and the communication paths between them are controlled by specific miRNAs in immune cells, neurons or glia. Therefore, nucleotide sequences mimicking or antagonizing miRNA actions can provide novel therapeutic strategies for pain treatment, provided their human homologues serve the same or at least similar functions. Similar clinical applications can be expected for tools targeting lncRNAs, which converge so far mainly on purinergic signaling pathways both in neurons and glia, and possibly even for other ncRNA species that have not been explored so far.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the Austrian Science Fund (FWF) [grant number P30809 (to K.K.)], and DK-SPIN W1206-06, P253450 and the European Commission [grant number 602133] (to M.K.).

Abbreviations

     
  • CRPS

    complex regional pain syndrome

  •  
  • DPN

    diabetic painful neuropathy

  •  
  • lncRNA

    long non-coding RNA

  •  
  • miRNA

    microRNA

  •  
  • ncRNA

    non-coding RNA

References

References
1.
Sadosky
A.
,
McDermott
A.M.
,
Brandenburg
N.A.
and
Strauss
M.
(
2008
)
A review of the epidemiology of painful diabetic peripheral neuropathy, postherpetic neuralgia, and less commonly studied neuropathic pain conditions
.
Pain Pract.: Off. J. World Inst. Pain
8
,
45
56
[PubMed]
2.
Sommer
C.
(
2003
)
Painful neuropathies
.
Curr. Opin. Neurol.
16
,
623
628
[PubMed]
3.
Vincent
A.M.
,
Callaghan
B.C.
,
Smith
A.L.
and
Feldman
E.L.
(
2011
)
Diabetic neuropathy: cellular mechanisms as therapeutic targets
.
Nat. Rev. Neurol.
7
,
573
583
[PubMed]
4.
Pabreja
K.
,
Dua
K.
,
Sharma
S.
,
Padi
S.S.
and
Kulkarni
S.K.
(
2011
)
Minocycline attenuates the development of diabetic neuropathic pain: possible anti-inflammatory and anti-oxidant mechanisms
.
Eur. J. Pharmacol.
661
,
15
21
[PubMed]
5.
Birch
R.
,
Misra
P.
,
Stewart
M.P.
,
Eardley
W.G.
,
Ramasamy
A.
,
Brown
K.
et al.
(
2012
)
Nerve injuries sustained during warfare: part I–Epidemiology
.
J. Bone Joint Sur. Br. Vol.
94
,
523
528
[PubMed]
6.
Ciaramitaro
P.
,
Mondelli
M.
,
Logullo
F.
,
Grimaldi
S.
,
Battiston
B.
,
Sard
A.
et al.
(
2010
)
Traumatic peripheral nerve injuries: epidemiological findings, neuropathic pain and quality of life in 158 patients
.
J. Peripher. Nerv. Syst.: JPNS
15
,
120
127
[PubMed]
7.
Myers
R.R.
,
Campana
W.M.
and
Shubayev
V.I.
(
2006
)
The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets
.
Drug Discov. Today
11
,
8
20
[PubMed]
8.
Parkitny
L.
,
McAuley
J.H.
,
Di Pietro
F.
,
Stanton
T.R.
,
O'Connell
N.E.
,
Marinus
J.
et al.
(
2013
)
Inflammation in complex regional pain syndrome: a systematic review and meta-analysis
.
Neurology
80
,
106
117
[PubMed]
9.
Marinus
J.
,
Moseley
G.L.
,
Birklein
F.
,
Baron
R.
,
Maihofner
C.
,
Kingery
W.S.
et al.
(
2011
)
Clinical features and pathophysiology of complex regional pain syndrome
.
Lancet Neurol.
10
,
637
648
[PubMed]
10.
Fischer
S.G.
,
Zuurmond
W.W.
,
Birklein
F.
,
Loer
S.A.
and
Perez
R.S.
(
2010
)
Anti-inflammatory treatment of Complex Regional Pain Syndrome
.
Pain
151
,
251
256
[PubMed]
11.
Uceyler
N.
,
Eberle
T.
,
Rolke
R.
,
Birklein
F.
and
Sommer
C.
(
2007
)
Differential expression patterns of cytokines in complex regional pain syndrome
.
Pain
132
,
195
205
[PubMed]
12.
O'Connor
R.M.
,
Dinan
T.G.
and
Cryan
J.F.
(
2012
)
Little things on which happiness depends: microRNAs as novel therapeutic targets for the treatment of anxiety and depression
.
Mol. Psychiatry
17
,
359
376
[PubMed]
13.
Soreq
H.
and
Wolf
Y.
(
2011
)
NeurimmiRs: microRNAs in the neuroimmune interface
.
Trends Mol. Med.
17
,
548
555
[PubMed]
14.
Barbash
S.
and
Soreq
H.
(
2012
)
Threshold-independent meta-analysis of Alzheimer's disease transcriptomes shows progressive changes in hippocampal functions, epigenetics and microRNA regulation
.
Current Alzheimer Res.
9
,
425
435
[PubMed]
15.
Baron
R.
,
Forster
M.
and
Binder
A.
(
2012
)
Subgrouping of patients with neuropathic pain according to pain-related sensory abnormalities: a first step to a stratified treatment approach
.
Lancet Neurol.
11
,
999
1005
[PubMed]
16.
Beggs
S.
,
Liu
X.J.
,
Kwan
C.
and
Salter
M.W.
(
2010
)
Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier
.
Mol. Pain
6
,
74
[PubMed]
17.
Beggs
S.
,
Trang
T.
and
Salter
M.W.
(
2012
)
P2X4R+ microglia drive neuropathic pain
.
Nat. Neurosci.
15
,
1068
1073
[PubMed]
18.
Berta
T.
,
Poirot
O.
,
Pertin
M.
,
Ji
R.R.
,
Kellenberger
S.
and
Decosterd
I.
(
2008
)
Transcriptional and functional profiles of voltage-gated Na(+) channels in injured and non-injured DRG neurons in the SNI model of neuropathic pain
.
Mol. Cell. Neurosci.
37
,
196
208
[PubMed]
19.
Bierhaus
A.
,
Fleming
T.
,
Stoyanov
S.
,
Leffler
A.
,
Babes
A.
,
Neacsu
C.
et al.
(
2012
)
Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy
.
Nat. Med.
18
,
926
933
[PubMed]
20.
Goebel
A.
(
2011
)
Complex regional pain syndrome in adults
.
Rheumatology (Oxford, England)
50
,
1739
1750
[PubMed]
21.
Mutso
A.A.
,
Radzicki
D.
,
Baliki
M.N.
,
Huang
L.
,
Banisadr
G.
,
Centeno
M.V.
et al.
(
2012
)
Abnormalities in hippocampal functioning with persistent pain
.
J. Neurosci.
32
,
5747
5756
[PubMed]
22.
Cardoso
A.L.
,
Guedes
J.R.
and
de Lima
M.C.
(
2016
)
Role of microRNAs in the regulation of innate immune cells under neuroinflammatory conditions
.
Curr. Opin. Pharmacol.
26
,
1
9
[PubMed]
23.
Lee
Y.
,
Jeon
K.
,
Lee
J.T.
,
Kim
S.
and
Kim
V.N.
(
2002
)
MicroRNA maturation: stepwise processing and subcellular localization
.
EMBO J.
21
,
4663
4670
[PubMed]
24.
Han
J.
,
Lee
Y.
,
Yeom
K.H.
,
Kim
Y.K.
,
Jin
H.
and
Kim
V.N.
(
2004
)
The Drosha-DGCR8 complex in primary microRNA processing
.
Genes Dev.
18
,
3016
3027
25.
Lee
Y.
,
Ahn
C.
,
Han
J.
,
Choi
H.
,
Kim
J.
,
Yim
J.
et al.
(
2003
)
The nuclear RNase III Drosha initiates microRNA processing
.
Nature
425
,
415
419
[PubMed]
26.
Melamed
Z.
,
Levy
A.
,
Ashwal-Fluss
R.
,
Lev-Maor
G.
,
Mekahel
K.
,
Atias
N.
et al.
(
2013
)
Alternative splicing regulates biogenesis of miRNAs located across exon-intron junctions
.
Mol. Cell
50
,
869
881
[PubMed]
27.
Alexiou
P.
,
Vergoulis
T.
,
Gleditzsch
M.
,
Prekas
G.
,
Dalamagas
T.
,
Megraw
M.
et al.
(
2010
)
miRGen 2.0: a database of microRNA genomic information and regulation
.
Nucleic Acids Res.
38
,
D137
D141
[PubMed]
28.
Zeidler
M.
,
Hüttenhofer
A.
,
Kress
M.
and
Kummer
K.K.
Intragenic microRNAs autoregulate their host genes in both direct and indirect ways - a cross-species analysis
29.
Godnic
I.
,
Zorc
M.
,
Jevsinek Skok
D.
,
Calin
G.A.
,
Horvat
S.
,
Dovc
P.
et al.
(
2013
)
Genome-wide and species-wide in silico screening for intragenic MicroRNAs in human, mouse and chicken
.
PLoS ONE
8
,
e65165
[PubMed]
30.
Franca
G.S.
,
Vibranovski
M.D.
and
Galante
P.A.
(
2016
)
Host gene constraints and genomic context impact the expression and evolution of human microRNAs
.
Nat. Commun.
7
,
11438
[PubMed]
31.
Hori
N.
,
Narita
M.
,
Yamashita
A.
,
Horiuchi
H.
,
Hamada
Y.
,
Kondo
T.
et al.
(
2016
)
Changes in the expression of IL-6-Mediated MicroRNAs in the dorsal root ganglion under neuropathic pain in mice
.
Synapse (New York, N.Y.).
70
,
317
324
[PubMed]
32.
Ha
M.
and
Kim
V.N.
(
2014
)
Regulation of microRNA biogenesis
.
Nat. Rev. Mol. Cell biol.
15
,
509
524
[PubMed]
33.
Treiber
T.
,
Treiber
N.
and
Meister
G.
(
2019
)
Regulation of microRNA biogenesis and its crosstalk with other cellular pathways
.
Nat. Rev. Mol. Cell Biol.
20
,
5
20
[PubMed]
34.
Brites
D.
and
Fernandes
A.
(
2015
)
Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation
.
Front. Cell. Neurosci.
9
,
476
[PubMed]
35.
Rao
P.
,
Benito
E.
and
Fischer
A.
(
2013
)
MicroRNAs as biomarkers for CNS disease
.
Front. Mol. Neurosci.
6
,
39
[PubMed]
36.
Simeoli
R.
,
Montague
K.
,
Jones
H.R.
,
Castaldi
L.
,
Chambers
D.
,
Kelleher
J.H.
et al.
(
2017
)
Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma
.
Nat. Commun.
8
,
1778
[PubMed]
37.
Ajit
S.K.
(
2012
)
Circulating microRNAs as biomarkers, therapeutic targets, and signaling molecules
.
Sensors (Basel, Switzerland).
12
,
3359
3369
[PubMed]
38.
Orlova
I.A.
,
Alexander
G.M.
,
Qureshi
R.A.
,
Sacan
A.
,
Graziano
A.
,
Barrett
J.E.
et al.
(
2011
)
MicroRNA modulation in complex regional pain syndrome
.
J. Transl. Med.
9
,
195
[PubMed]
39.
McDonald
M.K.
,
Tian
Y.
,
Qureshi
R.A.
,
Gormley
M.
,
Ertel
A.
,
Gao
R.
et al.
(
2014
)
Functional significance of macrophage-derived exosomes in inflammation and pain
.
Pain
155
,
1527
1539
[PubMed]
40.
Douglas
S.R.
,
Shenoda
B.B.
,
Qureshi
R.A.
,
Sacan
A.
,
Alexander
G.M.
,
Perreault
M.
et al.
(
2015
)
Analgesic Response to Intravenous Ketamine Is Linked to a Circulating microRNA Signature in Female Patients With Complex Regional Pain Syndrome
.
J. Pain: Off. J. Am. Pain Soc.
16
,
814
824
[PubMed]
41.
Ramanathan
S.
,
Douglas
S.R.
,
Alexander
G.M.
,
Shenoda
B.B.
,
Barrett
J.E.
,
Aradillas
E.
et al.
(
2019
)
Exosome microRNA signatures in patients with complex regional pain syndrome undergoing plasma exchange
.
J. Transl. Med.
17
,
81
[PubMed]
42.
Pasquier
J.
,
Ramachandran
V.
,
Abu-Qaoud
M.R.
,
Thomas
B.
,
Benurwar
M.J.
,
Chidiac
O.
et al.
(
2018
)
Differentially expressed circulating microRNAs in the development of acute diabetic Charcot foot
.
Epigenomics
10
,
1267
1278
[PubMed]
43.
Cheng
B.
,
Li
J.Y.
,
Li
X.C.
,
Wang
X.F.
,
Wang
Z.J.
,
Liu
J.
et al.
(
2018
)
MiR-323b-5p acts as a novel diagnostic biomarker for critical limb ischemia in type 2 diabetic patients
.
Sci. Rep.
8
,
15080
[PubMed]
44.
Li
J.Y.
,
Cheng
B.
,
Wang
X.F.
,
Wang
Z.J.
,
Zhang
H.M.
,
Liu
S.F.
et al.
(
2018
)
Circulating MicroRNA-4739 May Be a Potential Biomarker of Critical Limb Ischemia in Patients with Diabetes
.
Biomed. Res. Int.
2018
,
4232794
[PubMed]
45.
Santos-Bezerra
D.P.
,
Santos
A.S.
,
Guimaraes
G.C.
,
Admoni
S.N.
,
Perez
R.V.
,
Machado
C.G.
et al.
(
2019
)
Micro-RNAs 518d-3p and 618 Are Upregulated in Individuals With Type 1 Diabetes With Multiple Microvascular Complications
.
Front. Endocrinol.
10
,
385
[PubMed]
46.
Alles
J.
,
Fehlmann
T.
,
Fischer
U.
,
Backes
C.
,
Galata
V.
,
Minet
M.
et al.
(
2019
)
An estimate of the total number of true human miRNAs
.
Nucleic Acids Res.
47
,
3353
3364
[PubMed]
47.
Git
A.
,
Dvinge
H.
,
Salmon-Divon
M.
,
Osborne
M.
,
Kutter
C.
,
Hadfield
J.
et al.
(
2010
)
Systematic comparison of microarray profiling, real-time PCR, and next-generation sequencing technologies for measuring differential microRNA expression
.
RNA (New York, N.Y.).
16
,
991
1006
[PubMed]
48.
Hitzemann
R.
,
Bottomly
D.
,
Darakjian
P.
,
Walter
N.
,
Iancu
O.
,
Searles
R.
et al.
(
2013
)
Genes, behavior and next-generation RNA sequencing
.
Genes Brain Behavior
12
,
1
12
[PubMed]
49.
Kalpachidou
T.
,
Kummer
K.K.
,
Mitric
M.
and
Kress
M.
(
2019
)
Tissue Specific Reference Genes for MicroRNA Expression Analysis in a Mouse Model of Peripheral Nerve Injury
.
Front. Mol. Neurosci.
12
,
283
[PubMed]
50.
Herskovits
A.Z.
and
Guarente
L.
(
2014
)
SIRT1 in neurodevelopment and brain senescence
.
Neuron
81
,
471
483
[PubMed]
51.
Heyn
J.
,
Luchting
B.
,
Hinske
L.C.
,
Hubner
M.
,
Azad
S.C.
and
Kreth
S.
(
2016
)
miR-124a and miR-155 enhance differentiation of regulatory T cells in patients with neuropathic pain
.
J. Neuroinflammation
13
,
248
[PubMed]
52.
McDonald
M.K.
,
Ramanathan
S.
,
Touati
A.
,
Zhou
Y.
,
Thanawala
R.U.
,
Alexander
G.M.
et al.
(
2016
)
Regulation of proinflammatory genes by the circulating microRNA hsa-miR-939
.
Sci. Rep.
6
,
30976
[PubMed]
53.
Shenoda
B.B.
,
Alexander
G.M.
and
Ajit
S.K.
(
2016
)
Hsa-miR-34a mediated repression of corticotrophin releasing hormone receptor 1 regulates pro-opiomelanocortin expression in patients with complex regional pain syndrome
.
J. Transl. Med.
14
,
64
[PubMed]
54.
Leinders
M.
,
Uceyler
N.
,
Pritchard
R.A.
,
Sommer
C.
and
Sorkin
L.S.
(
2016
)
Increased miR-132-3p expression is associated with chronic neuropathic pain
.
Exp. Neurol.
283
,
276
286
[PubMed]
55.
Li
Y.B.
,
Wu
Q.
,
Liu
J.
,
Fan
Y.Z.
,
Yu
K.F.
and
Cai
Y.
(
2017
)
miR199a3p is involved in the pathogenesis and progression of diabetic neuropathy through downregulation of SerpinE2
.
Mol. Med. Rep.
16
,
2417
2424
[PubMed]
56.
Asahchop
E.L.
,
Branton
W.G.
,
Krishnan
A.
,
Chen
P.A.
,
Yang
D.
,
Kong
L.
et al.
(
2018
)
HIV-associated sensory polyneuropathy and neuronal injury are associated with miRNA-455-3p induction
.
JCI Insight.
3
,
e122450
[PubMed]
57.
Shenoda
B.B.
,
Tian
Y.
,
Alexander
G.M.
,
Aradillas-Lopez
E.
,
Schwartzman
R.J.
and
Ajit
S.K.
(
2018
)
miR-34a-mediated regulation of XIST in female cells under inflammation
.
J. Pain Res.
11
,
935
945
[PubMed]
58.
Liu
J.C.
,
Xue
D.F.
,
Wang
X.Q.
,
Ai
D.B.
and
Qin
P.J.
(
2019
)
MiR-101 relates to chronic peripheral neuropathic pain through targeting KPNB1 and regulating NF-kappaB signaling
.
Kaohsiung J. Med. Sci.
35
,
139
145
[PubMed]
59.
Aldrich
B.T.
,
Frakes
E.P.
,
Kasuya
J.
,
Hammond
D.L.
and
Kitamoto
T.
(
2009
)
Changes in expression of sensory organ-specific microRNAs in rat dorsal root ganglia in association with mechanical hypersensitivity induced by spinal nerve ligation
.
Neuroscience
164
,
711
723
[PubMed]
60.
Bai
G.
,
Ambalavanar
R.
,
Wei
D.
and
Dessem
D.
(
2007
)
Downregulation of selective microRNAs in trigeminal ganglion neurons following inflammatory muscle pain
.
Mol. Pain
3
,
15
[PubMed]
61.
Bali
K.K.
,
Hackenberg
M.
,
Lubin
A.
,
Kuner
R.
and
Devor
M.
(
2014
)
Sources of individual variability: miRNAs that predispose to neuropathic pain identified using genome-wide sequencing
.
Mol. Pain
10
,
22
[PubMed]
62.
Kusuda
R.
,
Cadetti
F.
,
Ravanelli
M.I.
,
Sousa
T.A.
,
Zanon
S.
,
De Lucca
F.L.
et al.
(
2011
)
Differential expression of microRNAs in mouse pain models
.
Mol. Pain
7
,
17
[PubMed]
63.
Norcini
M.
,
Sideris
A.
,
Martin Hernandez
L.A.
,
Zhang
J.
,
Blanck
T.J.
and
Recio-Pinto
E.
(
2014
)
An approach to identify microRNAs involved in neuropathic pain following a peripheral nerve injury
.
Front. Neurosci.
8
,
266
[PubMed]
64.
von Schack
D.
,
Agostino
M.J.
,
Murray
B.S.
,
Li
Y.
,
Reddy
P.S.
,
Chen
J.
et al.
(
2011
)
Dynamic changes in the microRNA expression profile reveal multiple regulatory mechanisms in the spinal nerve ligation model of neuropathic pain
.
PLoS ONE
6
,
e17670
[PubMed]
65.
Poh
K.W.
,
Yeo
J.F.
and
Ong
W.Y.
(
2011
)
MicroRNA changes in the mouse prefrontal cortex after inflammatory pain
.
Eur. J. Pain
15
,
801.e801
812.e801
66.
Imai
S.
,
Saeki
M.
,
Yanase
M.
,
Horiuchi
H.
,
Abe
M.
,
Narita
M.
et al.
(
2011
)
Change in microRNAs associated with neuronal adaptive responses in the nucleus accumbens under neuropathic pain
.
J. Neurosci.
31
,
15294
15299
[PubMed]
67.
Cao
S.
,
Yuan
J.
,
Zhang
D.
,
Wen
S.
,
Wang
J.
,
Li
Y.
et al.
(
2019
)
Transcriptome Changes In Dorsal Spinal Cord Of Rats With Neuropathic Pain
.
J. Pain Res.
12
,
3013
3023
[PubMed]
68.
Malcangio
M.
(
2019
)
Role of the immune system in neuropathic pain
.
Scand. J. Pain
20, 33-37
[PubMed]
69.
Dai
D.
,
Wang
J.
,
Jiang
Y.
,
Yuan
L.
,
Lu
Y.
,
Zhang
A.
et al.
(
2019
)
Small RNA sequencing reveals microRNAs related to neuropathic pain in rats
.
Brazi. J. Med. Biol. Res. = Revista Brasileira de Pesquisas Medicas e Biologicas
52
,
e8380
[PubMed]
70.
Li
H.
,
Wan
H.Q.
,
Zhao
H.J.
,
Luan
S.X.
and
Zhang
C.G.
(
2019
)
Identification of candidate genes and miRNAs associated with neuropathic pain induced by spared nerve injury
.
Int. J. Mol. Med.
44
,
1205
1218
[PubMed]
71.
Sommer
C.
,
Leinders
M.
and
Uceyler
N.
(
2018
)
Inflammation in the pathophysiology of neuropathic pain
.
Pain
159
,
595
602
[PubMed]
72.
Ito
N.
,
Sakai
A.
,
Miyake
N.
,
Maruyama
M.
,
Iwasaki
H.
,
Miyake
K.
et al.
(
2017
)
miR-15b mediates oxaliplatin-induced chronic neuropathic pain through BACE1 down-regulation
.
Br. J. Pharmacol.
174
,
386
395
[PubMed]
73.
Sakai
A.
,
Saitow
F.
,
Maruyama
M.
,
Miyake
N.
,
Miyake
K.
,
Shimada
T.
et al.
(
2017
)
MicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain
.
Nat. Commun.
8
,
16079
[PubMed]
74.
Wu
H.
,
Wen
F.
,
Jiang
M.
,
Liu
Q.
and
Nie
Y.
(
2018
)
LncRNA uc.48+ is involved in the diabetic immune and inflammatory responses mediated by P2X7 receptor in RAW264.7 macrophages
.
Int. J. Mol. Med.
42
,
1152
1160
[PubMed]
75.
Yan
T.
,
Zhang
F.
,
Sun
C.
,
Sun
J.
,
Wang
Y.
,
Xu
X.
et al.
(
2018
)
miR-32-5p-mediated Dusp5 downregulation contributes to neuropathic pain
.
Biochem. Biophys. Res. Commun.
495
,
506
511
[PubMed]
76.
Lu
Y.
,
Cao
D.L.
,
Jiang
B.C.
,
Yang
T.
and
Gao
Y.J.
(
2015
)
MicroRNA-146a-5p attenuates neuropathic pain via suppressing TRAF6 signaling in the spinal cord
.
Brain Behav. Immun.
49
,
119
129
[PubMed]
77.
Tan
Y.
,
Yang
J.
,
Xiang
K.
,
Tan
Q.
and
Guo
Q.
(
2015
)
Suppression of microRNA-155 attenuates neuropathic pain by regulating SOCS1 signalling pathway
.
Neurochem. Res.
40
,
550
560
[PubMed]
78.
Yang
S.
,
Krug
S.M.
,
Heitmann
J.
,
Hu
L.
,
Reinhold
A.K.
,
Sauer
S.
et al.
(
2016
)
Analgesic drug delivery via recombinant tissue plasminogen activator and microRNA-183-triggered opening of the blood-nerve barrier
.
Biomaterials
82
,
20
33
[PubMed]
79.
Wang
X.
,
Wang
H.
,
Zhang
T.
,
He
M.
,
Liang
H.
,
Wang
H.
et al.
(
2019
)
Inhibition of MicroRNA-195 Alleviates Neuropathic Pain by Targeting Patched1 and Inhibiting SHH Signaling Pathway Activation
.
Neurochem. Res.
44
,
1690
1702
[PubMed]
80.
Shi
G.
,
Shi
J.
,
Liu
K.
,
Liu
N.
,
Wang
Y.
,
Fu
Z.
et al.
(
2013
)
Increased miR-195 aggravates neuropathic pain by inhibiting autophagy following peripheral nerve injury
.
Glia
61
,
504
512
[PubMed]
81.
Li
L.
and
Zhao
G.
(
2016
)
Downregulation of microRNA-218 relieves neuropathic pain by regulating suppressor of cytokine signaling 3
.
Int. J. Mol. Med.
37
,
851
858
[PubMed]
82.
Xia
L.
,
Zhang
Y.
and
Dong
T.
(
2016
)
Inhibition of MicroRNA-221 Alleviates Neuropathic Pain Through Targeting Suppressor of Cytokine Signaling 1
.
J. Mol. Neurosci.
59
,
411
420
[PubMed]
83.
Yu
Y.
,
Zhu
M.
,
Zhao
Y.
,
Xu
M.
and
Qiu
M.
(
2018
)
Overexpression of TUSC7 inhibits the inflammation caused by microglia activation via regulating miR-449a/PPAR-gamma
.
Biochem. Biophys. Res. Commun.
503
,
1020
1026
[PubMed]
84.
Huang
Z.Z.
,
Wei
J.Y.
,
Ou-Yang
H.D.
,
Li
D.
,
Xu
T.
,
Wu
S.L.
et al.
(
2016
)
mir-500-Mediated GAD67 Downregulation Contributes to Neuropathic Pain
.
J. Neurosci.
36
,
6321
6331
[PubMed]
85.
Sakai
A.
,
Saitow
F.
,
Miyake
N.
,
Miyake
K.
,
Shimada
T.
and
Suzuki
H.
(
2013
)
miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability
.
Brain
136
,
2738
2750
[PubMed]
86.
Yang
F.R.
,
Chen
J.
,
Yi
H.
,
Peng
L.Y.
,
Hu
X.L.
and
Guo
Q.L.
(
2019
)
MicroRNA-7a ameliorates neuropathic pain in a rat model of spinal nerve ligation via the neurofilament light polypeptide-dependent signal transducer and activator of transcription signaling pathway
.
Mol. Pain
15
,
1744806919842464
[PubMed]
87.
Jiang
J.
,
Hu
Y.
,
Zhang
B.
,
Shi
Y.
,
Zhang
J.
,
Wu
X.
et al.
(
2017
)
MicroRNA-9 regulates mammalian axon regeneration in peripheral nerve injury
.
Mol. Pain
13
,
1744806917711612
[PubMed]
88.
Manners
M.T.
,
Tian
Y.
,
Zhou
Z.
and
Ajit
S.K.
(
2015
)
MicroRNAs downregulated in neuropathic pain regulate MeCP2 and BDNF related to pain sensitivity
.
FEBS Open Bio.
5
,
733
740
[PubMed]
89.
You
H.
,
Zhang
L.
,
Chen
Z.
,
Liu
W.
,
Wang
H.
and
He
H.
(
2019
)
MiR-20b-5p relieves neuropathic pain by targeting Akt3 in a chronic constriction injury rat model
.
Synapse (New York, N.Y.)
73
,
e22125
[PubMed]
90.
Zhong
L.
,
Xiao
W.
,
Wang
F.
,
Liu
J.
and
Zhi
L.J.
(
2019
)
miR-21-5p inhibits neuropathic pain development via directly targeting C-C motif ligand 1 and tissue inhibitor of metalloproteinase-3
.
J. Cell. Biochem.
120
,
16614
16623
[PubMed]
91.
Pan
Z.
,
Shan
Q.
,
Gu
P.
,
Wang
X.M.
,
Tai
L.W.
,
Sun
M.
et al.
(
2018
)
miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis
.
J. Neuroinflammation
15
,
29
[PubMed]
92.
Im
Y.B.
,
Jee
M.K.
,
Choi
J.I.
,
Cho
H.T.
,
Kwon
O.H.
and
Kang
S.K.
(
2012
)
Molecular targeting of NOX4 for neuropathic pain after traumatic injury of the spinal cord
.
Cell Death Dis.
3
,
e426
[PubMed]
93.
Zhang
Y.
,
Su
Z.
,
Liu
H.L.
,
Li
L.
,
Wei
M.
,
Ge
D.J.
et al.
(
2018
)
Effects of miR-26a-5p on neuropathic pain development by targeting MAPK6 in in CCI rat models
.
Biomed. Pharmacother.
107
,
644
649
[PubMed]
94.
Shao
J.
,
Cao
J.
,
Wang
J.
,
Ren
X.
,
Su
S.
,
Li
M.
et al.
(
2016
)
MicroRNA-30b regulates expression of the sodium channel Nav1.7 in nerve injury-induced neuropathic pain in the rat
.
Mol. Pain
12
, 1-13
[PubMed]
95.
Su
S.
,
Shao
J.
,
Zhao
Q.
,
Ren
X.
,
Cai
W.
,
Li
L.
et al.
(
2017
)
MiR-30b Attenuates Neuropathic Pain by Regulating Voltage-Gated Sodium Channel Nav1.3 in Rats
.
Front. Mol. Neurosci.
10
,
126
[PubMed]
96.
Brandenburger
T.
,
Johannsen
L.
,
Prassek
V.
,
Kuebart
A.
,
Raile
J.
,
Wohlfromm
S.
et al.
(
2019
)
MiR-34a is differentially expressed in dorsal root ganglia in a rat model of chronic neuropathic pain
.
Neurosci. Lett.
708
,
134365
[PubMed]
97.
Xu
L.
,
Wang
Q.
,
Jiang
W.
,
Yu
S.
and
Zhang
S.
(
2019
)
MiR-34c Ameliorates Neuropathic Pain by Targeting NLRP3 in a Mouse Model of Chronic Constriction Injury
.
Neuroscience
399
,
125
134
[PubMed]
98.
Chen
H.P.
,
Zhou
W.
,
Kang
L.M.
,
Yan
H.
,
Zhang
L.
,
Xu
B.H.
et al.
(
2014
)
Intrathecal miR-96 inhibits Nav1.3 expression and alleviates neuropathic pain in rat following chronic construction injury
.
Neurochem. Res.
39
,
76
83
[PubMed]
99.
Zhang
J.
,
Zhang
H.
and
Zi
T.
(
2015
)
Overexpression of microRNA-141 relieves chronic constriction injury-induced neuropathic pain via targeting high-mobility group box 1
.
Int. J. Mol. Med.
36
,
1433
1439
[PubMed]
100.
Zhang
Y.
,
Mou
J.
,
Cao
L.
,
Zhen
S.
,
Huang
H.
and
Bao
H.
(
2018
)
MicroRNA-142-3p relieves neuropathic pain by targeting high mobility group box 1
.
Int. J. Mol. Med.
41
,
501
510
[PubMed]
101.
Shi
J.
,
Jiang
K.
and
Li
Z.
(
2018
)
MiR-145 ameliorates neuropathic pain via inhibiting inflammatory responses and mTOR signaling pathway by targeting Akt3 in a rat model
.
Neurosci. Res.
134
,
10
17
[PubMed]
102.
Pang
X.
,
Tang
Y.
and
Zhang
D.
(
2016
)
Role of miR-145 in chronic constriction injury in rats
.
Exp. Ther. Med.
12
,
4121
4127
[PubMed]
103.
Zhou
X.
,
Zhang
C.
,
Zhang
C.
,
Peng
Y.
,
Wang
Y.
and
Xu
H.
(
2017
)
MicroRNA-182-5p Regulates Nerve Injury-induced Nociceptive Hypersensitivity by Targeting Ephrin Type-b Receptor 1
.
Anesthesiology
126
,
967
977
[PubMed]
104.
Xie
X.
,
Ma
L.
,
Xi
K.
,
Zhang
W.
and
Fan
D.
(
2017
)
MicroRNA-183 Suppresses Neuropathic Pain and Expression of AMPA Receptors by Targeting mTOR/VEGF Signaling Pathway
.
Cell. Physiol. Biochem.
41
,
181
192
[PubMed]
105.
Lin
C.R.
,
Chen
K.H.
,
Yang
C.H.
,
Huang
H.W.
and
Sheen-Chen
S.M.
(
2014
)
Intrathecal miR-183 delivery suppresses mechanical allodynia in mononeuropathic rats
.
Eur. J. Neurosci.
39
,
1682
1689
[PubMed]
106.
Shi
D.N.
,
Yuan
Y.T.
,
Ye
D.
,
Kang
L.M.
,
Wen
J.
and
Chen
H.P.
(
2018
)
MiR-183-5p Alleviates Chronic Constriction Injury-Induced Neuropathic Pain Through Inhibition of TREK-1
.
Neurochem. Res.
43
,
1143
1149
[PubMed]
107.
Jiang
B.C.
,
Cao
D.L.
,
Zhang
X.
,
Zhang
Z.J.
,
He
L.N.
,
Li
C.H.
et al.
(
2016
)
CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5
.
J. Clin. Invest.
126
,
745
761
[PubMed]
108.
Yang
D.
,
Yang
Q.
,
Wei
X.
,
Liu
Y.
,
Ma
D.
,
Li
J.
et al.
(
2017
)
The role of miR-190a-5p contributes to diabetic neuropathic pain via targeting SLC17A6
.
J. Pain Res.
10
,
2395
2403
[PubMed]
109.
Yan
X.T.
,
Zhao
Y.
,
Cheng
X.L.
,
He
X.H.
,
Wang
Y.
,
Zheng
W.Z.
et al.
(
2018
)
Inhibition of miR-200b/miR-429 contributes to neuropathic pain development through targeting zinc finger E box binding protein-1
.
J. Cell. Physiol.
233
,
4815
4824
[PubMed]
110.
Sun
W.
,
Zhang
L.
and
Li
R.
(
2017
)
Overexpression of miR-206 ameliorates chronic constriction injury-induced neuropathic pain in rats via the MEK/ERK pathway by targeting brain-derived neurotrophic factor
.
Neurosci. Lett.
646
,
68
74
[PubMed]
111.
Wen
J.
,
He
T.
,
Qi
F.
and
Chen
H.
(
2019
)
MiR-206-3p alleviates chronic constriction injury-induced neuropathic pain through targeting HDAC4
.
Exp. Anim.
68
,
213
220
[PubMed]
112.
Hu
Y.
,
Liu
Q.
,
Zhang
M.
,
Yan
Y.
,
Yu
H.
and
Ge
L.
(
2019
)
MicroRNA-362-3p attenuates motor deficit following spinal cord injury via targeting paired box gene 2
.
J. Integr. Neurosci.
18
,
57
64
[PubMed]
113.
Lu
S.
,
Ma
S.
,
Wang
Y.
,
Huang
T.
,
Zhu
Z.
and
Zhao
G.
(
2017
)
Mus musculus-microRNA-449a ameliorates neuropathic pain by decreasing the level of KCNMA1 and TRPA1, and increasing the level of TPTE
.
Mol. Med. Rep.
16
,
353
360
[PubMed]
114.
Ding
M.
,
Shen
W.
and
Hu
Y.
(
2017
)
The Role of miR-539 in the Anterior Cingulate Cortex in Chronic Neuropathic Pain
.
Pain Med.
18
,
2433
2442
[PubMed]
115.
Goldie
B.J.
and
Cairns
M.J.
(
2012
)
Post-transcriptional trafficking and regulation of neuronal gene expression
.
Mol. Neurobiol.
45
,
99
108
[PubMed]
116.
Hansen
T.B.
,
Jensen
T.I.
,
Clausen
B.H.
,
Bramsen
J.B.
,
Finsen
B.
,
Damgaard
C.K.
et al.
(
2013
)
Natural RNA circles function as efficient microRNA sponges
.
Nature
495
,
384
388
[PubMed]
117.
Park
C.K.
,
Xu
Z.Z.
,
Berta
T.
,
Han
Q.
,
Chen
G.
,
Liu
X.J.
et al.
(
2014
)
Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1
.
Neuron
82
,
47
54
[PubMed]
118.
Jeong
H.
,
Na
Y.J.
,
Lee
K.
,
Kim
Y.H.
,
Lee
Y.
,
Kang
M.
et al.
(
2016
)
High-resolution transcriptome analysis reveals neuropathic pain gene-expression signatures in spinal microglia after nerve injury
.
Pain
157
,
964
976
[PubMed]
119.
Reinhold
A.K.
,
Schwabe
J.
,
Lux
T.J.
,
Salvador
E.
and
Rittner
H.L.
(
2018
)
Quantitative and Microstructural Changes of the Blood-Nerve Barrier in Peripheral Neuropathy
.
Front. Neurosci.
12
,
936
[PubMed]
120.
Hervera
A.
,
De Virgiliis
F.
,
Palmisano
I.
,
Zhou
L.
,
Tantardini
E.
,
Kong
G.
et al.
(
2018
)
Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons
.
Nat. Cell Biol.
20
,
307
319
[PubMed]
121.
Zhao
J.
,
Lee
M.C.
,
Momin
A.
,
Cendan
C.M.
,
Shepherd
S.T.
,
Baker
M.D.
et al.
(
2010
)
Small RNAs control sodium channel expression, nociceptor excitability, and pain thresholds
.
J. Neurosci.
30
,
10860
10871
[PubMed]
122.
Li
X.
,
Gibson
G.
,
Kim
J.S.
,
Kroin
J.
,
Xu
S.
,
van Wijnen
A.J.
et al.
(
2011
)
MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis
.
Gene
480
,
34
41
[PubMed]
123.
Favereaux
A.
,
Thoumine
O.
,
Bouali-Benazzouz
R.
,
Roques
V.
,
Papon
M.A.
,
Salam
S.A.
et al.
(
2011
)
Bidirectional integrative regulation of Cav1.2 calcium channel by microRNA miR-103: role in pain
.
EMBO J.
30
,
3830
3841
[PubMed]
124.
Zhang
Z.J.
,
Guo
J.S.
,
Li
S.S.
,
Wu
X.B.
,
Cao
D.L.
,
Jiang
B.C.
et al.
(
2018
)
TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG
.
J. Exp. Med.
215
,
3019
3037
[PubMed]
125.
Langeslag
M.
,
Malsch
P.
,
Welling
A.
and
Kress
M.
(
2014
)
Reduced excitability of gp130-deficient nociceptors is associated with increased voltage-gated potassium currents and Kcna4 channel upregulation
.
Pflugers Arch.
466
,
2153
2165
[PubMed]
126.
Namer
B.
,
Orstavik
K.
,
Schmidt
R.
,
Mair
N.
,
Kleggetveit
I.P.
,
Zeidler
M.
et al.
(
2017
)
Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype
.
Front. Neurol.
8
,
335
[PubMed]
127.
Cai
L.
,
Liu
X.
,
Guo
Q.
,
Huang
Q.
,
Zhang
Q.
and
Cao
Z.
(
2019
)
MiR-15a attenuates peripheral nerve injury-induced neuropathic pain by targeting AKT3 to regulate autophagy
.
Genes Genomics
42
,
77
85
128.
Merighi
A.
,
Salio
C.
,
Ghirri
A.
,
Lossi
L.
,
Ferrini
F.
,
Betelli
C.
et al.
(
2008
)
BDNF as a pain modulator
.
Prog. Neurobiol.
85
,
297
317
[PubMed]
129.
Thompson
S.W.
,
Bennett
D.L.
,
Kerr
B.J.
,
Bradbury
E.J.
and
McMahon
S.B.
(
1999
)
Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord
.
Proc. Natl. Acad. Sci. U.S.A.
96
,
7714
7718
[PubMed]
130.
McMahon
S.B.
and
Priestley
J.V.
(
1995
)
Peripheral neuropathies and neurotrophic factors: animal models and clinical perspectives
.
Curr. Opin. Neurobiol.
5
,
616
624
[PubMed]
131.
Geranton
S.M.
,
Morenilla-Palao
C.
and
Hunt
S.P.
(
2007
)
A role for transcriptional repressor methyl-CpG-binding protein 2 and plasticity-related gene serum- and glucocorticoid-inducible kinase 1 in the induction of inflammatory pain states
.
J. Neurosci.
27
,
6163
6173
[PubMed]
132.
Lin
Y.T.
,
Ro
L.S.
,
Wang
H.L.
and
Chen
J.C.
(
2011
)
Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitro study
.
J. Neuroinflammation
8
,
126
[PubMed]
133.
Crow
M.
,
Khovanov
N.
,
Kelleher
J.H.
,
Sharma
S.
,
Grant
A.D.
,
Bogdanov
Y.
et al.
(
2015
)
HDAC4 is required for inflammation-associated thermal hypersensitivity
.
FASEB J.
29
,
3370
3378
[PubMed]
134.
Bai
G.
,
Wei
D.
,
Zou
S.
,
Ren
K.
and
Dubner
R.
(
2010
)
Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia
.
Mol. Pain
6
,
51
[PubMed]
135.
Lin
T.B.
,
Hsieh
M.C.
,
Lai
C.Y.
,
Cheng
J.K.
,
Chau
Y.P.
,
Ruan
T.
et al.
(
2015
)
Modulation of Nerve Injury-induced HDAC4 Cytoplasmic Retention Contributes to Neuropathic Pain in Rats
.
Anesthesiology
123
,
199
212
[PubMed]
136.
Willemen
H.L.
,
Huo
X.J.
,
Mao-Ying
Q.L.
,
Zijlstra
J.
,
Heijnen
C.J.
and
Kavelaars
A.
(
2012
)
MicroRNA-124 as a novel treatment for persistent hyperalgesia
.
J. Neuroinflammation
9
,
143
[PubMed]
137.
Yu
W.
,
Zhao
G.Q.
,
Cao
R.J.
,
Zhu
Z.H.
and
Li
K.
(
2017
)
LncRNA NONRATT021972 Was Associated with Neuropathic Pain Scoring in Patients with Type 2 Diabetes
.
Behav. Neurol.
2017
,
2941297
[PubMed]
138.
Ohayon
D.
,
Venteo
S.
,
Sonrier
C.
,
Lafon
P.A.
,
Garces
A.
,
Valmier
J.
et al.
(
2015
)
Zeb family members and boundary cap cells underlie developmental plasticity of sensory nociceptive neurons
.
Dev. Cell
33
,
343
350
[PubMed]
139.
Li
D.
,
Lang
W.
,
Zhou
C.
,
Wu
C.
,
Zhang
F.
,
Liu
Q.
et al.
(
2018
)
Upregulation of Microglial ZEB1 Ameliorates Brain Damage after Acute Ischemic Stroke
.
Cell Rep.
22
,
3574
3586
[PubMed]
140.
Farley
J.E.
,
Burdett
T.C.
,
Barria
R.
,
Neukomm
L.J.
,
Kenna
K.P.
,
Landers
J.E.
et al.
(
2018
)
Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration
.
Proc. Natl. Acad. Sci. U.S.A.
115
,
1358
1363
[PubMed]
141.
Hu
Y.
,
Mai
W.
,
Chen
L.
,
Cao
K.
,
Zhang
B.
,
Zhang
Z.
et al.
(
2019
)
mTOR-mediated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP
.
Glia
68
,
1031
1045
142.
Iyer
A.
,
Zurolo
E.
,
Prabowo
A.
,
Fluiter
K.
,
Spliet
W.G.
,
van Rijen
P.C.
et al.
(
2012
)
MicroRNA-146a: a key regulator of astrocyte-mediated inflammatory response
.
PLoS ONE
7
,
e44789
[PubMed]
143.
Lu
Y.
,
Jiang
B.C.
,
Cao
D.L.
,
Zhang
Z.J.
,
Zhang
X.
,
Ji
R.R.
et al.
(
2014
)
TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-alpha and IL-1beta signaling
.
Pain
155
,
2618
2629
[PubMed]
144.
Lugli
G.
,
Larson
J.
,
Martone
M.E.
,
Jones
Y.
and
Smalheiser
N.R.
(
2005
)
Dicer and eIF2c are enriched at postsynaptic densities in adult mouse brain and are modified by neuronal activity in a calpain-dependent manner
.
J. Neurochem.
94
,
896
905
[PubMed]
145.
Sim
S.E.
,
Bakes
J.
and
Kaang
B.K.
(
2014
)
Neuronal activity-dependent regulation of MicroRNAs
.
Mol. Cells
37
,
511
517
[PubMed]
146.
Song
X.J.
,
Zheng
J.H.
,
Cao
J.L.
,
Liu
W.T.
,
Song
X.S.
and
Huang
Z.J.
(
2008
)
EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats
.
Pain
139
,
168
180
[PubMed]
147.
Hung
T.Y.
,
Chu
F.L.
,
Wu
D.C.
,
Wu
S.N.
and
Huang
C.W.
(
2019
)
The Protective Role of Peroxisome Proliferator-Activated Receptor-Gamma in Seizure and Neuronal Excitotoxicity
.
Mol. Neurobiol.
56
,
5497
5506
[PubMed]
148.
Wang
L.
,
Chen
S.R.
,
Ma
H.
,
Chen
H.
,
Hittelman
W.N.
and
Pan
H.L.
(
2018
)
Regulating nociceptive transmission by VGluT2-expressing spinal dorsal horn neurons
.
J. Neurochem.
147
,
526
540
[PubMed]
149.
Scherrer
G.
,
Low
S.A.
,
Wang
X.
,
Zhang
J.
,
Yamanaka
H.
,
Urban
R.
et al.
(
2010
)
VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity
.
Proc. Natl. Acad. Sci. U.S.A.
107
,
22296
22301
[PubMed]
150.
Liu
Y.
,
Abdel Samad
O.
,
Zhang
L.
,
Duan
B.
,
Tong
Q.
,
Lopes
C.
et al.
(
2010
)
VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch
.
Neuron
68
,
543
556
[PubMed]
151.
Cheng
L.
,
Arata
A.
,
Mizuguchi
R.
,
Qian
Y.
,
Karunaratne
A.
,
Gray
P.A.
et al.
(
2004
)
Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates
.
Nat. Neurosci.
7
,
510
517
[PubMed]
152.
Meisner
J.G.
,
Marsh
A.D.
and
Marsh
D.R.
(
2010
)
Loss of GABAergic interneurons in laminae I-III of the spinal cord dorsal horn contributes to reduced GABAergic tone and neuropathic pain after spinal cord injury
.
J. Neurotrauma
27
,
729
737
[PubMed]
153.
Parsons
M.J.
,
Grimm
C.H.
,
Paya-Cano
J.L.
,
Sugden
K.
,
Nietfeld
W.
,
Lehrach
H.
et al.
(
2008
)
Using hippocampal microRNA expression differences between mouse inbred strains to characterise miRNA function
.
Mammalian Genome: Off. J. Int. Mammalian Genome Soc.
19
,
552
560
[PubMed]
154.
Bredy
T.W.
,
Lin
Q.
,
Wei
W.
,
Baker-Andresen
D.
and
Mattick
J.S.
(
2011
)
MicroRNA regulation of neural plasticity and memory
.
Neurobiol. Learn. Mem.
96
,
89
94
[PubMed]
155.
Edbauer
D.
,
Neilson
J.R.
,
Foster
K.A.
,
Wang
C.F.
,
Seeburg
D.P.
,
Batterton
M.N.
et al.
(
2010
)
Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132
.
Neuron
65
,
373
384
[PubMed]
156.
Saba
R.
,
Storchel
P.H.
,
Aksoy-Aksel
A.
,
Kepura
F.
,
Lippi
G.
,
Plant
T.D.
et al.
(
2012
)
Dopamine-regulated microRNA MiR-181a controls GluA2 surface expression in hippocampal neurons
.
Mol. Cell. Biol.
32
,
619
632
[PubMed]
157.
Numakawa
T.
,
Yamamoto
N.
,
Chiba
S.
,
Richards
M.
,
Ooshima
Y.
,
Kishi
S.
et al.
(
2011
)
Growth factors stimulate expression of neuronal and glial miR-132
.
Neurosci. Lett.
505
,
242
247
[PubMed]
158.
Kawashima
H.
,
Numakawa
T.
,
Kumamaru
E.
,
Adachi
N.
,
Mizuno
H.
,
Ninomiya
M.
et al.
(
2010
)
Glucocorticoid attenuates brain-derived neurotrophic factor-dependent upregulation of glutamate receptors via the suppression of microRNA-132 expression
.
Neuroscience
165
,
1301
1311
[PubMed]
159.
Haramati
S.
,
Navon
I.
,
Issler
O.
,
Ezra-Nevo
G.
,
Gil
S.
,
Zwang
R.
et al.
(
2011
)
MicroRNA as repressors of stress-induced anxiety: the case of amygdalar miR-34
.
J. Neurosci.
31
,
14191
14203
[PubMed]
160.
Shaltiel
G.
,
Hanan
M.
,
Wolf
Y.
,
Barbash
S.
,
Kovalev
E.
,
Shoham
S.
et al.
(
2013
)
Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target
.
Brain Struct. Funct.
218
,
59
72
161.
Ni
J.
,
Gao
Y.
,
Gong
S.
,
Guo
S.
,
Hisamitsu
T.
and
Jiang
X.
(
2013
)
Regulation of mu-opioid type 1 receptors by microRNA134 in dorsal root ganglion neurons following peripheral inflammation
.
Eur. J. Pain (London, England)
17
,
313
323
[PubMed]
162.
Sengupta
J.N.
,
Pochiraju
S.
,
Kannampalli
P.
,
Bruckert
M.
,
Addya
S.
,
Yadav
P.
et al.
(
2013
)
MicroRNA-mediated GABA Aalpha-1 receptor subunit down-regulation in adult spinal cord following neonatal cystitis-induced chronic visceral pain in rats
.
Pain
154
,
59
70
[PubMed]
163.
He
Y.
,
Yang
C.
,
Kirkmire
C.M.
and
Wang
Z.J.
(
2010
)
Regulation of opioid tolerance by let-7 family microRNA targeting the mu opioid receptor
.
J. Neurosci.
30
,
10251
10258
[PubMed]
164.
Wu
Q.
,
Hwang
C.K.
,
Zheng
H.
,
Wagley
Y.
,
Lin
H.Y.
,
Kim
D.K.
et al.
(
2013
)
MicroRNA 339 down-regulates mu-opioid receptor at the post-transcriptional level in response to opioid treatment
.
FASEB J.
27
,
522
535
[PubMed]
165.
Fang
S.
,
Zhang
L.
,
Guo
J.
,
Niu
Y.
,
Wu
Y.
,
Li
H.
et al.
(
2018
)
NONCODEV5: a comprehensive annotation database for long non-coding RNAs
.
Nucleic Acids Res.
46
,
D308
D314
[PubMed]
166.
Ma
L.
,
Cao
J.
,
Liu
L.
,
Du
Q.
,
Li
Z.
,
Zou
D.
et al.
(
2019
)
LncBook: a curated knowledgebase of human long non-coding RNAs
.
Nucleic Acids Res.
47
,
D128
D134
[PubMed]
167.
Fernandes
J.C.R.
,
Acuña
S.M.
,
Aoki
J.I.
,
Floeter-Winter
L.M.
and
Muxel
S.M.
(
2019
)
Long Non-Coding RNAs in the Regulation of Gene Expression: Physiology and Disease
.
Noncoding RNA
5
,
17
168.
Dahariya
S.
,
Paddibhatla
I.
,
Kumar
S.
,
Raghuwanshi
S.
,
Pallepati
A.
and
Gutti
R.K.
(
2019
)
Long non-coding RNA: Classification, biogenesis and functions in blood cells
.
Mol. Immunol.
112
,
82
92
[PubMed]
169.
Quinn
J.J.
and
Chang
H.Y.
(
2016
)
Unique features of long non-coding RNA biogenesis and function
.
Nat. Rev. Genet.
17
,
47
62
[PubMed]
170.
Yang
J.X.
,
Rastetter
R.H.
and
Wilhelm
D.
(
2016
)
Non-coding RNAs: An Introduction
.
Adv. Exp. Med. Biol.
886
,
13
32
[PubMed]
171.
Jarroux
J.
,
Morillon
A.
and
Pinskaya
M.
(
2017
)
History, Discovery, and Classification of lncRNAs
.
Adv. Exp. Med. Biol.
1008
,
1
46
[PubMed]
172.
Carlevaro-Fita
J.
and
Johnson
R.
(
2019
)
Global Positioning System: Understanding Long Noncoding RNAs through Subcellular Localization
.
Mol. Cell
73
,
869
883
[PubMed]
173.
Schmitz
S.U.
,
Grote
P.
and
Herrmann
B.G.
(
2016
)
Mechanisms of long noncoding RNA function in development and disease
.
Cell. Mol. Life Sci.
73
,
2491
2509
[PubMed]
174.
Luo
L.
,
Ji
L.D.
,
Cai
J.J.
,
Feng
M.
,
Zhou
M.
,
Hu
S.P.
et al.
(
2018
)
Microarray Analysis of Long Noncoding RNAs in Female Diabetic Peripheral Neuropathy Patients
.
Cell. Physiol. Biochem.
46
,
1209
1217
[PubMed]
175.
Suwal
A.
,
Hao
J.L.
,
Liu
X.F.
,
Zhou
D.D.
,
Pant
O.P.
,
Gao
Y.
et al.
(
2019
)
NONRATT021972 long-noncoding RNA: A promising lncRNA in diabetes-related diseases
.
Int. J. Med. Sci.
16
,
902
908
[PubMed]
176.
Wang
L.
,
Luo
T.
,
Bao
Z.
,
Li
Y.
and
Bu
W.
(
2018
)
Intrathecal circHIPK3 shRNA alleviates neuropathic pain in diabetic rats
.
Biochem. Biophys. Res. Commun.
505
,
644
650
[PubMed]
177.
Peng
H.
,
Zou
L.
,
Xie
J.
,
Wu
H.
,
Wu
B.
,
Zhu
G.
et al.
(
2017
)
lncRNA NONRATT021972 siRNA Decreases Diabetic Neuropathic Pain Mediated by the P2X3 Receptor in Dorsal Root Ganglia
.
Mol. Neurobiol.
54
,
511
523
[PubMed]
178.
Wang
S.
,
Xu
H.
,
Zou
L.
,
Xie
J.
,
Wu
H.
,
Wu
B.
et al.
(
2016
)
LncRNA uc.48+ is involved in diabetic neuropathic pain mediated by the P2X3 receptor in the dorsal root ganglia
.
Purinergic Signal.
12
,
139
148
[PubMed]
179.
Wu
B.
,
Zhang
C.
,
Zou
L.
,
Ma
Y.
,
Huang
K.
,
Lv
Q.
et al.
(
2016
)
LncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats mediated by P2X7 receptor in SCG
.
Autonomic Neurosci.: Basic Clin.
197
,
14
18
180.
Yu
B.
,
Zhou
S.
,
Hu
W.
,
Qian
T.
,
Gao
R.
,
Ding
G.
et al.
(
2013
)
Altered long noncoding RNA expressions in dorsal root ganglion after rat sciatic nerve injury
.
Neurosci. Lett.
534
,
117
122
[PubMed]
181.
Mao
P.
,
Li
C.R.
,
Zhang
S.Z.
,
Zhang
Y.
,
Liu
B.T.
and
Fan
B.F.
(
2018
)
Transcriptomic differential lncRNA expression is involved in neuropathic pain in rat dorsal root ganglion after spared sciatic nerve injury
.
Brazil. J. Med. Biol. Res. = Revista Brasileira de Pesquisas Medicas e Biologicas
51
,
e7113
[PubMed]
182.
Baskozos
G.
,
Dawes
J.M.
,
Austin
J.S.
,
Antunes-Martins
A.
,
McDermott
L.
,
Clark
A.J.
et al.
(
2019
)
Comprehensive analysis of long noncoding RNA expression in dorsal root ganglion reveals cell-type specificity and dysregulation after nerve injury
.
Pain
160
,
463
485
[PubMed]
183.
Zhou
J.
,
Fan
Y.
and
Chen
H.
(
2017
)
Analyses of long non-coding RNA and mRNA profiles in the spinal cord of rats using RNA sequencing during the progression of neuropathic pain in an SNI model
.
RNA Biol.
14
,
1810
1826
[PubMed]
184.
Jiang
B.C.
,
Sun
W.X.
,
He
L.N.
,
Cao
D.L.
,
Zhang
Z.J.
and
Gao
Y.J.
(
2015
)
Identification of lncRNA expression profile in the spinal cord of mice following spinal nerve ligation-induced neuropathic pain
.
Mol. Pain
11
,
43
[PubMed]
185.
Pan
B.
,
Zhou
H.X.
,
Liu
Y.
,
Yan
J.Y.
,
Wang
Y.
,
Yao
X.
et al.
(
2017
)
Time-dependent differential expression of long non-coding RNAs following peripheral nerve injury
.
Int. J. Mol. Med.
39
,
1381
1392
[PubMed]
186.
Raju
H.B.
,
Englander
Z.
,
Capobianco
E.
,
Tsinoremas
N.F.
and
Lerch
J.K.
(
2014
)
Identification of potential therapeutic targets in a model of neuropathic pain
.
Front. Genet.
5
,
131
[PubMed]
187.
Wang
W.-T.
,
Sun
Y.-M.
,
Huang
W.
,
He
B.
,
Zhao
Y.-N.
and
Chen
Y.-Q.
(
2016
)
Genome-wide Long Non-coding RNA Analysis Identified Circulating LncRNAs as Novel Non-invasive Diagnostic Biomarkers for Gynecological Disease
.
Sci. Rep.
6
,
23343
[PubMed]
188.
Li
Y.
,
Li
Q.
,
Wang
C.
,
Li
S.
and
Yu
L.
(
2019
)
Long Noncoding RNA Expression Profile in BV2 Microglial Cells Exposed to Lipopolysaccharide
.
Biomed. Res. Int.
2019
,
5387407
[PubMed]
189.
Xu
S.
,
Ao
J.
,
Gu
H.
,
Wang
X.
,
Xie
C.
,
Meng
D.
et al.
(
2017
)
IL-22 Impedes the Proliferation of Schwann cells: Transcriptome Sequencing and Bioinformatics Analysis
.
Mol. Neurobiol.
54
,
2395
2405
[PubMed]
190.
Iwasaki
H.
,
Sakai
A.
,
Maruyama
M.
,
Ito
T.
,
Sakamoto
A.
and
Suzuki
H.
(
2019
)
Increased H19 Long Non-coding RNA Expression in Schwann Cells in Peripheral Neuropathic Pain
.
J. Nippon Med. Sch.
86
,
215
221
[PubMed]
191.
Liu
C.L.
,
Deng
Z.Y.
,
Du
E.R.
and
Xu
C.S.
(
2018
)
Long noncoding RNA BC168687 small interfering RNA reduces high glucose and high free fatty acidinduced expression of P2X7 receptors in satellite glial cells
.
Mol. Med. Rep.
17
,
5851
5859
[PubMed]
192.
Liu
C.
,
Li
C.
,
Deng
Z.
,
Du
E.
and
Xu
C.
(
2018
)
Long Non-coding RNA BC168687 is Involved in TRPV1-mediated Diabetic Neuropathic Pain in Rats
.
Neuroscience
374
,
214
222
[PubMed]
193.
Liu
C.
,
Tao
J.
,
Wu
H.
,
Yang
Y.
,
Chen
Q.
,
Deng
Z.
et al.
(
2017
)
Effects of LncRNA BC168687 siRNA on Diabetic Neuropathic Pain Mediated by P2X7 Receptor on SGCs in DRG of Rats
.
Biomed. Res. Int.
2017
,
7831251
[PubMed]
194.
Li
G.
,
Jiang
H.
,
Zheng
C.
,
Zhu
G.
,
Xu
Y.
,
Sheng
X.
et al.
(
2017
)
Long noncoding RNA MRAK009713 is a novel regulator of neuropathic pain in rats
.
Pain
158
,
2042
2052
[PubMed]
195.
Liu
S.
,
Zou
L.
,
Xie
J.
,
Xie
W.
,
Wen
S.
,
Xie
Q.
et al.
(
2016
)
LncRNA NONRATT021972 siRNA regulates neuropathic pain behaviors in type 2 diabetic rats through the P2X7 receptor in dorsal root ganglia
.
Mol. Brain
9
,
44
[PubMed]
196.
Hu
J.Z.
,
Rong
Z.J.
,
Li
M.
,
Li
P.
,
Jiang
L.Y.
,
Luo
Z.X.
et al.
(
2019
)
Silencing of lncRNA PKIA-AS1 Attenuates Spinal Nerve Ligation-Induced Neuropathic Pain Through Epigenetic Downregulation of CDK6 Expression
.
Front. Cell. Neurosci.
13
,
50
[PubMed]
197.
Xiong
W.
,
Tan
M.
,
Tong
Z.
,
Yin
C.
,
He
L.
,
Liu
L.
et al.
(
2019
)
Effects of long non-coding RNA uc.48+ on pain transmission in trigeminal neuralgia
.
Brain Res. Bull.
147
,
92
100
[PubMed]
198.
Zhao
X.
,
Tang
Z.
,
Zhang
H.
,
Atianjoh
F.E.
,
Zhao
J.Y.
,
Liang
L.
et al.
(
2013
)
A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons
.
Nat. Neurosci.
16
,
1024
1031
[PubMed]
199.
Martinez-Moreno
M.
,
O'Shea
T.M.
,
Zepecki
J.P.
,
Olaru
A.
,
Ness
J.K.
,
Langer
R.
et al.
(
2017
)
Regulation of Peripheral Myelination through Transcriptional Buffering of Egr2 by an Antisense Long Non-coding RNA
.
Cell Rep.
20
,
1950
1963
[PubMed]
200.
Wu
S.
,
Marie Lutz
B.
,
Miao
X.
,
Liang
L.
,
Mo
K.
,
Chang
Y.J.
et al.
(
2016
)
Dorsal root ganglion transcriptome analysis following peripheral nerve injury in mice
.
Mol. Pain.
12
, 1-14
201.
Guo
G.
,
Ren
S.
,
Kang
Y.
,
Liu
Y.
,
Duscher
D.
,
Machens
H.G.
et al.
(
2019
)
Microarray analyses of lncRNAs and mRNAs expression profiling associated with diabetic peripheral neuropathy in rats
.
J. Cell. Biochem.
120
,
15347
15359
[PubMed]
202.
Zhao
X.
,
Tang
Z.
,
Zhang
H.
,
Atianjoh
F.E.
,
Zhao
J.-Y.
,
Liang
L.
et al.
(
2013
)
A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons
.
Nat. Neurosci.
16
,
1024
[PubMed]
203.
Xiong
W.
,
Tan
M.
,
Tong
Z.
,
Yin
C.
,
He
L.
,
Liu
L.
et al.
(
2019
)
Effects of long non-coding RNA uc.48+ on pain transmission in trigeminal neuralgia
.
Brain Res. Bull.
147
,
92
100
[PubMed]
204.
Yao
C.
,
Wang
J.
,
Zhang
H.
,
Zhou
S.
,
Qian
T.
,
Ding
F.
et al.
(
2015
)
Long non-coding RNA uc.217 regulates neurite outgrowth in dorsal root ganglion neurons following peripheral nerve injury
.
Eur. J. Neurosci.
42
,
1718
1725
[PubMed]
205.
Liu
Z.
,
Liang
Y.
,
Wang
H.
,
Lu
Z.
,
Chen
J.
,
Huang
Q.
et al.
(
2017
)
LncRNA expression in the spinal cord modulated by minocycline in a mouse model of spared nerve injury
.
J. Pain Res.
10
,
2503
2514
[PubMed]
206.
Zhou
J.
,
Xiong
Q.
,
Chen
H.
,
Yang
C.
and
Fan
Y.
(
2017
)
Identification of the Spinal Expression Profile of Non-coding RNAs Involved in Neuropathic Pain Following Spared Nerve Injury by Sequence Analysis
.
Front. Mol. Neurosci.
10
,
91
[PubMed]
207.
Cao
S.
,
Deng
W.
,
Li
Y.
,
Qin
B.
,
Zhang
L.
,
Yu
S.
et al.
(
2017
)
Chronic constriction injury of sciatic nerve changes circular RNA expression in rat spinal dorsal horn
.
J. Pain Res.
10
,
1687
1696
[PubMed]
208.
Du
H.
,
Liu
Z.
,
Tan
X.
,
Ma
Y.
and
Gong
Q.
(
2019
)
Identification of the Genome-wide Expression Patterns of Long Non-coding RNAs and mRNAs in Mice with Streptozotocin-induced Diabetic Neuropathic Pain
.
Neuroscience
402
,
90
103
[PubMed]
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