BioMed Research International

BioMed Research International / 2018 / Article

Review Article | Open Access

Volume 2018 |Article ID 5406973 | 10 pages |

Do MicroRNAs Modulate Visceral Pain?

Academic Editor: Eiichi Kumamoto
Received15 Jun 2018
Revised03 Sep 2018
Accepted16 Sep 2018
Published10 Oct 2018


Visceral pain, a common characteristic of multiple diseases relative to viscera, impacts millions of people worldwide. Although hundreds of studies have explored mechanisms underlying visceral pain, it is still poorly managed. Over the past decade, strong evidence emerged suggesting that microRNAs (miRNAs) play a significant role in visceral nociception through altering neurotransmitters, receptors and other genes at the posttranscriptional level. Under pathological conditions, one kind of miRNA may have several target mRNAs and several kinds of miRNAs may act on one target, suggesting complex interactions and mechanisms between miRNAs and target genes lead to pathological states. In this review we report on recent progress in examining miRNAs responsible for visceral sensitization and provide miRNA-based therapeutic targets for the management of visceral pain.

1. Introduction

Epigenetic modifications including DNA methylation, histone modifications, and noncoding RNAs can enhance or suppress gene expression pre- or post-transcriptionally without changing the primary DNA sequence [13]. Among noncoding RNAs, microRNA (miRNAs) are well studied and verified as contributing to pathological states, including cancer, cardiovascular, neurodegenerative, and autoimmune disease [47]. A 2007 study identified the involvement of miRNAs in the development and maintenance of orofacial inflammatory pain becoming the first report to explore the role of miRNAs in pain [8]. Over the subsequent decade, selective miRNAs acting on different target genes have been investigated in various pain disorders in both human conditions and animal models. The goal of this review is to update current knowledge on miRNAs in visceral pain and discuss the mechanisms involved, providing new potential targets for visceral pain management clinically.

2. Characteristics of Visceral Pain

Visceral pain, defined as pain originating from the internal organs, is a hallmark feature of multiple diseases and disorders including visceral inflammation (e.g., inflammatory bowel disease, pancreatitis, and appendicitis), occlusion of bile or urine flow (e.g., gallstones, kidney stones), reflux of stomach acid (e.g., gastroesophageal reflux disease), functional visceral disorders (e.g., irritable bowel syndrome (IBS), endometriosis, interstitial cystitis/bladder pain syndrome (IC/BPS), and functional dyspepsia), and ischemia (e.g., angina, colic) [916]. Visceral pain affects approximately 25% of people worldwide and is poorly managed clinically because it is typically defined as a symptom of another condition and not a disease itself [17].

Understanding the characteristics and pain pathways is useful to appreciate visceral pain modulation and potential therapeutics. Cervero and Laird first mentioned clinical features of visceral pain that discriminate it from somatic pain [18]. Visceral pain is not evoked from all viscera and may not be associated with tissue injury. Visceral pain can be produced by distending hollow organs, ischemia, or inflammation, but not stimuli which can induce somatic pain like crushing, cutting, or burning [19]. These noxious stimuli activate spinally projecting visceral afferent fibers (Aδ- and C-fibers) which terminate throughout the dorsoventral and mediolateral extent of the dorsal horn. Second-order neurons transmit the nociceptive information to the brain through multiple pathways including the spinothalamic, spinoreticular, spinoparabrachial tracts, and the postsynaptic dorsal columns-medial lemniscal pathway [2022]. Tertiary neurons in the thalamus and brainstem send ascending projections to different regions of the cortex and diencephalon which manage different aspects of visceral nociception. The primary and secondary somatosensory cortices confer sensory-discriminative aspects of pain perception (e.g., location, duration, quality, and intensity). Limbic structures (amygdala, insula, anterior and midcingulate cortex, and hypothalamus) manage affective and motivational aspects of pain. Compared with somatic pain, visceral pain is diffuse and hard to accurately localize. It refers to other locations on the body because the afferent fibers from one viscera may converge in the spinal cord with fibers from other visceral organs and nonvisceral tissues, which induces cross-organ sensitization through viscerovisceral and viscerasomatic convergence [23, 24]. Cortical output in response to pain activates descending pain regulatory circuitry in the brain stem and leads to the release of neurotransmitters in the dorsal horn of the spinal cord to regulate pain.

3. The Pathway of miRNA Maturation

miRNAs are small, single-stranded RNAs of about 22 nucleotides (nt). miRNAs can inhibit the expression of target genes to regulate protein expression at the post-transcriptional level [2527]. The mechanism of this inhibition is that miRNAs complementarily bind with target mRNAs at the 3’ untranslated regions (3’UTR) to block or suppress translation [28]. The miRNA biogenesis is complex and each step of the process is precisely regulated [29].

The classic pathway of miRNA biogenesis is generally known and shows a stepwise maturation pattern from the nucleus to the cytoplasm (Figure 1). miRNAs are thought to be transcribed from DNA that is not translated encompassing introns of coding genes, noncoding genes, and intergenic regions of genome [3032]. But some miRNAs can also be encoded on exons since they have an overlap with transcription units [30, 33]. The classic pathway of miRNA maturation in mammalian cells can be generalized into 5 steps. First, the primary miRNA (pri-miRNA) is transcribed from host DNA by Type-II or Type-III RNA polymerases, which add a polyglandular (Poly A) tail at the 3’ end, a 7-methylguanosine (7 mG) cap at the 5’ end and a characteristic stem-loop structure [31, 3437]. Second, the pri-miRNA transcript is processed in the nucleus by Drosha (a nuclear RNase) and DGCR8 (DiGeorge syndrome critical region 8, a RNA-binding protein) to a precursor miRNA (pre-miRNA) [28, 3840]. The specific mechanism of this step is that the Drosha microprocessor complex recognizes the base of the stem-loop structure of the pri-miRNA and cleaves it to form a double-stranded pre-miRNA, which is about 70–90 nt long [28]. Third, the pre-miRNA is exported from the nucleus to the cytoplasm by exportin-5 (Exp-5, Ran-binding protein 21) and Ras-related nuclear protein (Ran) [41, 42]. Ran changes into the Ran-guanine triphosphatase (Ran-GTP) state and then the pre-miRNA/Exp-5/Ran-GTP complex is translocated to the cytoplasm through a nuclear pore complex [43]. Fourth, once in the cytoplasm, the RNase III enzyme Dicer, together with the TAR RNA-binding protein (TRBP) and protein activator of PKR (PACT) cleave the pre-miRNA into a 22 nt long imperfect double-stranded RNA with a 2 nt overhang at each of its 3’ ends by removing the hairpin loop of the pre-miRNA [44]. One of the two strands is the mature miRNA (the guide strand) and the other one is the passenger strand (miRNA) [28, 36, 43]. Fifth, the mature miRNA combines with Argonaute (Ago) family proteins through the 2 nt 3’ overhang to form the functional center of an RNA-induced silencing complex (RISC), which executes post-transcriptional gene silencing [45, 46]. If the 5’ region of the miRNA (2-8 nt) can completely complement with its target mRNA, the target mRNA degrades and the translation process stops [29, 45, 47, 48]. At other times, imperfect base pairing between the 5’ regions of the miRNA and its target mRNA leads to translation repression, which occurs mostly in animals [49]. Because of the partial complementarity between miRNAs and mRNAs, one miRNA may act on several target mRNAs and several miRNAs may target one mRNA. The miRNA does not change into a RISC complex and is discarded [50]. Occasionally, miRNAs can also bind to the 5’ UTRs [51, 52] and even coding regions [5355] of target mRNAs. Most miRNAs reduce protein expression, but some miRNAs can enhance translation such as miR369-3 and miR-373, which suggests complex mechanisms of miRNAs involved in gene regulation [56, 57].

Besides the classic pathway of miRNA biogenesis, a growing number of alternative miRNA pathways have been identified [58, 59]. The most important alternative miRNA maturation pathway is the “mirtron” pathway which does not depend on pri-miRNA Drosha/DGCR8 processing. The mirtron is spliced out from an inframe intron with a transient lariat shape that the 3’ branch point is ligated to the 5’ end of the intron. The lariat debranching enzyme (Ldbr) processes the lariat-shape intron into the pre-miRNA shape and then the pre-miRNA is transferred to the cytoplasm by Exp-5 [58]. Mirtrons share the same extra nuclear maturation process as the classic pathway of miRNAs.

4. The Role of miRNA in Visceral Pain

Since miRNAs can regulate target genes and proteins posttranscriptionally, it may participate in visceral pain processing through regulating neurotransmitters and their receptors as well as other proteins peripherally or centrally. To our knowledge, the role of miRNAs in visceral pain was first studied in BPS, which showed a correlation between the miRNAs miR-449b, miR-500, miR-328, and miR-320 and neurokinin 1 (NK1) receptor expression in BPS patients [70]. After that, many other miRNAs were reported as regulators in different animal models of visceral pain and human visceral pain disorders, including endometriosis, BPS/IC, IBS, and acute chest pain (Table 1).

Diseases miRNAsTissuesTargetsReferences

IBSmiR-199 ↓Human colon; Rat colon/DRGTRPV1 ↑[60]
miR-24 ↑Human/mouse intestinal mucosaSERT ↓[61]
miR-17-5p ↑Lumbar spinal cordSTAT3↓; gp130↑[62]
miR-150 ↑
miR-342-3p ↑
Human whole blood-[63]
miR-29a ↑Human small bowel and colon; human blood macrovesiclesGlutamate ammonia
ligase ↓
miR-144 ↑Rat distal colonic epithelial cellsOccludin ↓; ZO1 ↓[65]

EndometriosismiR-9 ↓;
miR-34 ↓
Human endometrial tissues-[66]
miR-142-3p ↑Endometrial stroma cellsSteroid sulfatase ↓;
gp130 ↓
miR-29 ↑;
miR-181 ↑;
let-7 ↑
ox-LDL treated human endometrial cell-linesNGF ↑; IL-6 ↑;
miR-122 ↑;
miR-199a ↑
Serum; peritoneal fluid-[69]

BPS/ICmiR-449b ↑
miR-500 ↑
Bladder smooth muscle cellsNK1 receptor↓[70]
miR-199a-5p ↑Bladder smooth muscle;
Mature bladder urothelium;
Primary urothelial culture
LIN7C ↓;
PALS1 ↓;
RND1↓; PVRL1 ↓
miR-214 ↓Postmenopausal women’s bladder tissue;
Ovariectomized rats’ APMSCs
Mfn2 ↑;[72]
miR-139-5p ↓Postmenopausal women’s bladder tissueLPAR4 ↑[73]
miR-181a ↑Rat spinal cord[74]
miR-92b-3p ↑Rat spinal cordKCC2↓; VGAT ↓[75]

Recent progress in understanding interventional functions of miRNAs facilitates examination of underlying mechanisms and translational potential. Technologies allowing accurate deletion of significant enzymes of miRNA synthesis or inhibition of specific miRNAs are getting more mature. Conditional deletion of Dicer in the dorsal root ganglion by using Nav1.8-Cre mice leads to the attenuation of nociception-related gene expression and the reduction of inflammatory pain while maintaining intact acute nociception [76]. Inhibition of specific miRNAs by administrating miRNA sponge lentivirus with inhibitor sequences provides a novel method to study the mechanisms of single miRNA accurately [60, 75].

4.1. miRNAs in Colonic Pain

IBS is a common gastrointestinal disorder characterized by chronic colonic pain. IBS afflicts 10-20% of the world population and is widely studied by gastroenterologists and researchers for its underlying mechanisms [7779]. The etiology of IBS has been investigated ranging from early life stress, psychological disorders, and environmental effects to genetic factors [8083]. IBS can be divided into three types by its changes in bowel habits, including chronic abdominal pain with frequent occurrence of diarrhea (IBS-D), constipation (IBS-C), or mixed bowel habits (IBS-M)[84].

A clinical study in IBS-D patients has emphasized the importance of miR-199 in visceral pain [60]. Specifically, gut miR-199a/b expression in IBS-D patients was significantly decreased, which was correlated directly with both increased visceral pain scores and TRPV1 expression. In a rodent model, intraperitoneal administration of lenti-miR-199a precursors upregulated miR-199a and decreased visceral hypersensitivity by attenuating TRPV1 signaling. Thus miR-199 precursors may be a promising therapeutic candidate for the treatment of IBS-D [60]. In another study, miR-24 was upregulated in intestinal mucosa epithelial cells of both IBS-D patients and a mouse model of trinitro-benzene-sulfonic acid induced IBS [61]. The authors identified that the serotonin reuptake transporter (SERT), which transports 5-hydroxytryptamine (5-HT, serotonin) from synaptic spaces into presynaptic neurons and removes 5-HT from the interstitial space, was a potential target gene of miR-24 through a luciferase reporter assay [61, 85, 86]. In a chronic stress induced-visceral pain model, there was a significant increase in the interleukin-6 (IL-6) signal transducer glycoprotein 130 (gp130) and miR-17-5p expression in the spinal cord while the signal transducer and activator of transcription 3 (STAT3) as well as glial fibrillary acidic protein (GFAP) expression significantly decreased [62]. STAT3 and gp130 are predicted to be targets of miR-17-5p and gp130 was upregulated with the increase of miR-17-5p. It is known that stress is able to downregulate spinal GFAP which is associated with changes in the expression of several molecules related to glutamatergic signaling, glutamine synthase, and proinflammatory cytokines [87]. The study suggests that there is a possible link between increased expression of miR-17-5p and activation of gp130/STAT3/GFAP, leading to neuroinflammation in visceral hypersensitivity conditions [62]. Another study identified the role of miR-150 and miR-342-3p in IBS [63]. Though the downstream proteins still remain to be determined, these two miRNAs are thought to be dysregulated in IBS and linked to pain and inflammatory processes [63]. However, in blood samples from endometriosis patients, the expression of miR-199 increases and miR-17-5p decreases compared to healthy controls, suggesting contradictory results to those in IBS studies [88]. It remains to be determined if alterations of specific miRNAs in the circulatory system, nervous system, and pathological tissues perform different functions.

Some studies reported that miRNAs contribute to intestinal hyperpermeability of IBS-D patients. In a clinical study, it was reported that in 42% of IBS patients, intestinal membrane permeability increased, which was correlated with an increase of miR-29a in the small bowel, colon tissues and blood microvesicles [64]. Moreover, the study identified that miR-29a interacted with complementary binding sites at the 3’UTR of the glutamate ammonia ligase gene, which led to the decrease of glutamine synthase [64]. Colonic glutamine helps maintain the intestinal barrier and reduce bacterial translocation. Thus, downregulation of glutamine synthase leads to increased intestinal permeability and chronic colonic hypersensitivity. In a study based on a 4% acetic acid-induced IBS-D rodent model, miR-144 was markedly upregulated and resulted in the downregulation of its target genes, occludin and zonula occludens 1 (ZO1), and two tight junction proteins, which regulate the colonic intracellular and paracellular permeability, respectively [65, 89, 90]. Under pathological conditions, specific miRNAs target genes contribute to intestinal epithelial barrier function and lead to visceral hypersensitivity through modulating intestinal permeability. Thus, miRNAs may be the potential diagnostic and therapeutic targets for IBS.

4.2. miRNAs in Pelvic Pain

miRNAs have been widely studied in pelvic pain. Endometriosis affects 5%–10% of premenopausal women worldwide but is not well managed [91, 92]. It is pathologically characterized by the presence of endometrial glands and stroma implanted outside the uterine cavity and may be asymptomatic or present with a wide range of symptoms including infertility, dysmenorrhea, pelvic pain, pelvic mass, and cancerous lesions [9395]. However, the clinical diagnosis and pain management of endometriosis remain difficult due to the lack of understanding of underlying mechanisms [96].

A genome-wide association study (GWAS) on women with dysmenorrhea pain has identified one GWAS association at 1q13.2 that colocalizes with nerve growth factor (NGF), a neurotrophin linked to pain pathophysiology. This indicates that female pelvic pain severity is partly genetically determined [97]. Recently, the epigenetic mechanisms involved in endometriosis have also been widely studied. An early clinical study showed that miR-9 and miR-34 families were downregulated in endometrial tissues of women with painful endometriosis, but the downstream genes of the miRNAs regulation were not determined [66]. In a subsequent in vitro endometrial stroma cell study, an increase of miR-142-3p induced a significant decrease of steroid sulfatase and gp130 as well as deactivation of the IL-6-mediated inflammatory STAT3-pathway, resulting in decreased cell viability [67]. A recent study found that oxidized-lipoprotein (ox-LDL) levels in peritoneal fluid were related to maintenance of endometriotic lesions and nociception [68]. Specifically, the ox-LDL treatment of human endometrial cell-lines caused significant overexpression of nociceptive and inflammatory genes including NGF, IL-6, and prostaglandin E synthase 3 (PTGES3), as well as differential expression of 20 miRNAs including isoforms of miR-29, miR-181, and let-7 compared to control. These results were similar to the endometriotic tissues from endometriosis patients with pain compared to those without pain [68]. A prospective cohort study on women with endometriosis and those with pelvic pain but without the diagnosis of endometriosis showed that the serum and peritoneal fluid levels of IL-6, miR-122, and miR-199a were significantly higher in the former. In this study, there was no evidence suggesting the association between the expression of miR-122, miR-199a, and the severity of pelvic pain, but it provided evidence that miRNAs might serve as biomarkers for discrimination of endometriosis and other types of pelvic pain [69]. A clinical study of another intractable pelvic pain, vestibulodynia (VBD), showed patients with comorbid VBD and IBS failed to exhibit a balance in pro- and anti-inflammatory cytokines, while VBD patients compensated by increasing anti-inflammatory cytokines [98]. Both of these patients differentially expressed several miRNAs in peripheral blood which were predicted to be important for pain. All these studies of miRNAs on painful endometriosis are weighted in inflammatory-related pathways which might be a significant cause of pain in endometriosis and miRNAs could be promising analgesia targets. The studies support pain-related miRNA alterations in local pathological endometrial tissues or circulating biomarkers, but whether miRNAs at the spinal level or supraspinal level participate in endometriosis is still unclear.

miRNA activity has also been reported in another type of pelvic pain, bladder pain. BPS, also known as IC, is a syndrome characterized by pelvic pain related to urinary urgency and urinary frequency with multiple etiologies attributed to a recurrent and chronic inflammatory status of the muscle and submucosa of the bladder [99]. The specific etiology of BPS is not fully understood though pathogenic mechanisms including neuroinflammatory, autoimmune, possibly infectious, or toxic agents have been hypothesized [100].

As mentioned above, the first study of miRNAs in BPS showed that long-time exposure of bladder smooth muscle cells to substance P decreased NK1 receptor mRNA expression and concomitantly increased miR-449b and miR-500 [70]. The authors also identified this phenomenon in BPS patients and found that miR-449b and miR-500 increased, which indicated that activation of specific miRNAs caused an attenuation of NK1 receptor synthesis in BPS [70]. Using laser microdissection, Monastyrskaya et al. emphasized a possible association between miR-199a-5p expression and urothelial permeability in BPS patients [71]. Specifically, upregulation of miR-199a-5p and its concomitant downregulation of target genes, including LIN7C, ARHGAP12, PALS1, RND1, and PVRL1, might impact the urothelial barrier to induce defects in urothelial integrity leading to chronic bladder pain [71]. Hyperpermeability might be a significant reason for pelvic pain of BPS similar to IBS. Epithelial mesenchymal transition (EMT) and fibrosis in the bladder wall might change the permeability of the bladder, partially contributing to bladder pain. Recently, two studies on IC in postmenopausal women identified the role of miRNAs in EMT and fibrosis in the development of IC [72, 73]. In IC bladder tissues from postmenopausal women, a decrease of miR-214 and an increase of its target mitofusin 2 (Mfn2) compared to the normal bladder tissues were demonstrated by immunohistochemistry. In order to mimic the environment of IC patients to understand the underlying mechanisms, the authors transfected adipose-derived mesenchymal stem cells extracted from ovariectomized rats with miR-214 inhibitors and found downregulation of N-cadherin, fibronectin, Twist1 (twist basic helix-loop-helix transcription factor 1), Snail, and vimentin and upregulation of Mfn2, E-cadherin, and ZO1, resulting in promoting EMT and fibrosis in the bladder wall [72]. Another study showed a decrease in miR-139-5p and an increase in its target lysophosphatidic acid receptor 4 (LPAR4) in IC bladder tissues. Tissue from the IC group also showed a significant increase in expression of phosphatidylinositol 3-kinase (PI3K), Akt, p-PI3K, p-Akt, N-cadherin, vimentin, transforming growth factor-β1 (TGF--β1), and connective tissue growth factor (CTGF) and a decrease in expression of E-cadherin compared to the control group. These findings suggest that downregulation of miR-139-5p may advance EMT and fibrosis of the bladder by targeting LPAR4 and its downstream PI3K/Akt signaling pathway in postmenopausal IC [73]. The findings of the role of miRNAs in EMT and fibrosis in IC including miR-214 and miR-139-5p provide a novel insight into IC treatment.

Early adverse life events may render an individual more vulnerable to suffer chronic visceral hypersensitivity because of a failure of adaptive or coping mechanisms which prepare the individual to endure subsequent traumas better. This is an area currently being explored by epigenetic research. A study based on a rodent model has identified the involvement of miRNA-mediated post-transcriptional regulation of the developing spinal -aminobutyric acid- (GABA-) ergic system in neonatal cystitis-induced chronic visceral pain in rats [74]. Specifically, intravesicular injection of zymosan into the rats’ bladder during early postnatal days induced neonatal cystitis and these rats showed upregulation of mature miR-181a in the L6-S1 spinal dorsal horn in adults. Further study demonstrated multiple complementary binding sites in miR-181a for receptor subunit gene and an increase in miR-181a downregulated receptor subunit gene and protein expression in the spinal cord [74]. Recently, this laboratory confirmed the role of the spinal GABAergic system in bladder pain using the same model. Zymosan treatment in neonates and adults induced a similar increase in expression of spinal miR-92b-3p and a subsequent decrease in expression of its two targets, potassium chloride cotransporter (KCC2) and vesicular GABA transporter (VGAT), contributing to bladder nociception [75]. The impairment of GABAergic inhibition plays a key role in the transition of acute to chronic pain and several GABA-associated components, including receptor subunits, KCC2, GABA synthesizing enzymes, and VGAT, have been reported to be involved in this process [101104]. miRNA-mediated post-transcriptional regulation of the spinal GABAergic system may contribute to the long-lasting pelvic pain of cystitis, which provides novel targets for treatment of intractable pelvic pain.

4.3. Circulating miRNA in Chest Pain

Coronary artery disease, a major cause of chest pain with high mortality and morbidity worldwide, is divided into two subtypes: stable coronary heart disease and acute coronary syndrome (ACS). ACS is the symptomatic, clinical presentation of coronary artery disease, approximately half resulting from acute myocardial infarction, which causes death or disability within the first hours [105, 106]. For this reason, it is essential to discriminate ACS from other types of chest pain. Previous studies were weighing in the roles of circulating miRNAs as biomarkers in diagnosis of ACS or acute myocardial infarction compared to traditional diagnostic indices such as clinical symptoms, ECG changes, and elevation of cardiac troponin [107, 108]. It was reported that expression of miR-208b, miR-499, miR-146, miR-106b/25 cluster, miR-21/590-5p family, miR-17/92a, miR-451, miR-132, miR-186, miR-122, miR-3149, miR-221-3p, miR-210, miR-941, and miR-3162-3p increased and expression of miR-150 and miR-145 decreased in peripheral blood of ACS patients [105, 109119]. Though these findings provide diagnostic value of circulating miRNAs in ACS, the role of miRNAs in acute chest pain management is still unknown and further studies are needed.

5. Conclusions and Future Strategies

Current clinical treatment of visceral pain is unsatisfactory. Studies on alterations of miRNAs involved in different types of visceral pain have revealed that they may contribute to proinflammatory states, attenuation of epithelial barrier function and impairment of GABAergic system function, verifying the status of miRNAs as important modulators in development and maintenance of visceral pain. However, most studies focus on miRNA alterations in local pathological tissue biopsies rather than the nervous system. Different miRNAs are involved in different types of visceral pain and diseases, resulting in complex and possibly discrete mechanisms. Thus, further studies are needed to explore the mechanisms underlying miRNAs contribution to visceral pain conditions at the spinal and supraspinal levels and explore new and effective treatment targets for visceral pain. Additionally, pain processing is always complex and may involve multiple mechanisms, and the interactions between miRNAs and other epigenetic mechanisms such as DNA methylation and histone acetylation remain to be determined. How miRNAs change by environmental cues and how their changes contribute to visceral pain are still unclear. Whether there are upstream regulatory mechanisms of miRNA alterations is also unclear. Because one miRNA may act on several target genes, avoiding the side effects which arise from other targets of the therapeutic miRNA is important, yet it is hardly studied. In conclusion, the literatures directly implicating miRNAs in visceral pain are still limited. More advanced animal models for different types of visceral pain or other visceral pain-related diseases are needed to be studied. Currently, there are still challenges for visceral pain treatment. The significant role of miRNAs underlying this disorder is becoming increasingly recognized; therefore it is believed that miRNAs will be a promising treatment target for visceral pain management.


ACS:Acute coronary syndrome
DGCR8:DiGeorge syndrome critical region 8
EMT:Epithelial mesenchymal transition
GABA:-aminobutyric acid
GFAP:Glial fibrillary acidic protein
gp130:Glycoprotein 130
IBS:Irritable bowel syndrome
IC/BPS:Interstitial cystitis/bladder pain syndrome
KCC2:Potassium chloride cotransporter
Ldbr:Lariat debranching enzyme
Mfn2:Mitofusin 2
NGF:Nerve growth factor
NK1:Neurokinin 1
PACT:Protein activator of double-stranded RNA-activated protein kinase
PI3K:Phosphatidylinositol 3-kinase
pre-miRNA:Precursor miRNA
pri-miRNA:Primary miRNA
PTGES3:Prostaglandin E synthase 3
SERT:Serotonin reuptake transporter
Ran:Ras-related nuclear protein
RISC:RNA-induced silencing complex
STAT3:Signal transducer and activator of transcription 3
TRBP:Transactivation response RNA-binding protein
UTR:Untranslated regions
VGAT:Vesicular GABA transporter
ZO1:Zonula occludens 1.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.


This work was supported by the National Natural Science Foundation of China (no. 81671097) and Shaanxi Province Natural Science Basic Research Foundation of China (no. 2016JM3015).


  1. A. Portela and M. Esteller, “Epigenetic modifications and human disease,” Nature Biotechnology, vol. 28, no. 10, pp. 1057–1068, 2010. View at: Publisher Site | Google Scholar
  2. M. A. Varela, T. C. Roberts, and M. J. A. Wood, “Epigenetics and ncRNAs in brain function and disease: mechanisms and prospects for therapy,” Neurotherapeutics, vol. 10, no. 4, pp. 621–631, 2013. View at: Publisher Site | Google Scholar
  3. J. Gräff, D. Kim, M. M. Dobbin, and T. Li-Huei, “Epigenetic Regulation of Gene Expression in Physiological and Pathological Brain Processes,” Physiological Reviews, vol. 91, no. 2, pp. 603–649, 2011. View at: Publisher Site | Google Scholar
  4. G. A. Calin, C. D. Dumitru, and M. Shimizu, “Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia,” in Proceedings of the National Academy of Sciences of the United States of America, vol. 99, pp. 15524–15529. View at: Google Scholar
  5. E. van Rooij, L. B. Sutherland, and N. Liu, “A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 103, no. 48, pp. 18255–18260, 2006. View at: Publisher Site | Google Scholar
  6. Y. Dai, Y.-S. Huang, M. Tang et al., “Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients,” Lupus, vol. 16, no. 12, pp. 939–946, 2007. View at: Publisher Site | Google Scholar
  7. A. Schaefer, D. O'Carroll, L. T. Chan et al., “Cerebellar neurodegeneration in the absence of microRNAs,” The Journal of Experimental Medicine, vol. 204, no. 7, pp. 1553–1558, 2007. View at: Publisher Site | Google Scholar
  8. G. Bai, R. Ambalavanar, D. Wei, and D. Dessem, “Downregulation of selective microRNAs in trigeminal ganglion neurons following inflammatory muscle pain,” Molecular Pain, vol. 3, article no. 15, 2007. View at: Publisher Site | Google Scholar
  9. M. A. Giamberardino, R. Valente, P. de Bigontina, and L. Vecchiet, “Artificial ureteral calculosis in rats: behavioural characterization of visceral pain episodes and their relationship with referred lumbar muscle hyperalgesia,” PAIN, vol. 61, no. 3, pp. 459–469, 1995. View at: Publisher Site | Google Scholar
  10. M. Handa, H. Nukina, K. Ando, and C. Kubo, “What does pain or discomfort in irritable bowel syndrome mean?” Digestive Diseases and Sciences, vol. 49, no. 4, pp. 575–578, 2004. View at: Publisher Site | Google Scholar
  11. A. D. Farmer and Q. Aziz, “Visceral pain hypersensitivity in functional gastrointestinal disorders,” British Medical Bulletin, vol. 91, no. 1, pp. 123–136, 2009. View at: Publisher Site | Google Scholar
  12. P. Vercellini, E. Somigliana, P. Viganò, A. Abbiati, G. Barbara, and L. Fedele, “Chronic pelvic pain in women: etiology, pathogenesis and diagnostic approach,” Gynecological Endocrinology, vol. 25, no. 3, pp. 149–158, 2009. View at: Publisher Site | Google Scholar
  13. C. P. Gyawali, “Esophageal hypersensitivity,” Gastroenterol Hepatol, vol. 6, no. 8, pp. 497–500, 2010. View at: Google Scholar
  14. R. Fass and S. R. Achem, “Noncardiac chest pain: Epidemiology, natural course and pathogenesis,” Journal of Neurogastroenterology and Motility, vol. 17, no. 2, pp. 110–123, 2011. View at: Publisher Site | Google Scholar
  15. A. D. Farmer and Q. Aziz, “Gut pain & visceral hypersensitivity,” British Journal of Pain, vol. 7, no. 1, pp. 39–47, 2013. View at: Publisher Site | Google Scholar
  16. B. Greenwood-Van Meerveld, D. K. Prusator, and A. C. Johnson, “Animal models of gastrointestinal and liver diseases. Animal models of visceral pain: Pathophysiology, translational relevance, and challenges,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 308, no. 11, pp. G885–G903, 2015. View at: Publisher Site | Google Scholar
  17. R. D. Moloney, S. M. O'Mahony, T. G. Dinan, and J. F. Cryan, “Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities,” Frontiers in Psychiatry, vol. 6, article no. 15, 2015. View at: Publisher Site | Google Scholar
  18. F. Cervero and J. M. A. Laird, “Visceral pain,” The Lancet, vol. 353, no. 9170, pp. 2145–2148, 1999. View at: Publisher Site | Google Scholar
  19. T. J. Ness and G. F. Gebhart, “Visceral pain: a review of experimental studies,” PAIN, vol. 41, no. 2, pp. 167–234, 1990. View at: Publisher Site | Google Scholar
  20. A. Sharma, D. Lelic, C. Brock, P. Paine, and Q. Aziz, “New technologies to investigate the brain-gut axis,” World Journal of Gastroenterology, vol. 15, no. 2, pp. 182–191, 2009. View at: Publisher Site | Google Scholar
  21. D. A. Drossman, “Functional abdominal pain syndrome,” Clinical Gastroenterology and Hepatology, vol. 2, no. 5, pp. 353–365, 2004. View at: Publisher Site | Google Scholar
  22. T. F. Almeida, S. Roizenblatt, and S. Tufik, “Afferent pain pathways: A neuroanatomical review,” Brain Research, vol. 1000, no. 1-2, pp. 40–56, 2004. View at: Publisher Site | Google Scholar
  23. E. S. Schwartz and G. F. Gebhart, “Visceral Pain,” Current Topics in Behavioral Neurosciences, vol. 20, pp. 171–197, 2014. View at: Google Scholar
  24. S. J. Vanner, B. Greenwood-Van Meerveld, G. M. Mawe et al., “Fundamentals of neurogastroenterology: Basic science,” Gastroenterology, vol. 150, no. 6, pp. 1280–1291, 2016. View at: Publisher Site | Google Scholar
  25. V. N. Kim, J. Han, and M. C. Siomi, “Biogenesis of small RNAs in animals,” Nature Reviews Molecular Cell Biology, vol. 10, no. 2, pp. 126–139, 2009. View at: Publisher Site | Google Scholar
  26. J. Krol, I. Loedige, and W. Filipowicz, “The widespread regulation of microRNA biogenesis, function and decay,” Nature Reviews Genetics, vol. 11, no. 9, pp. 597–610, 2010. View at: Publisher Site | Google Scholar
  27. N. Tran and G. Hutvagner, “Biogenesis and the regulation of the maturation of miRNAs,” Essays in Biochemistry, vol. 54, no. 1, pp. 17–28, 2013. View at: Publisher Site | Google Scholar
  28. S. Ying, D. C. Chang, and S. Lin, “The MicroRNA,” Methods Mol Biol, vol. 936, pp. 1–19, 2013. View at: Publisher Site | Google Scholar
  29. M. Ha and V. N. Kim, “Regulation of microRNA biogenesis,” Nature Reviews Molecular Cell Biology, vol. 15, pp. 509–524, 2014. View at: Publisher Site | Google Scholar
  30. Y. K. Kim and V. N. Kim, “Processing of intronic microRNAs,” EMBO Journal, vol. 26, no. 3, pp. 775–783, 2007. View at: Publisher Site | Google Scholar
  31. B. C. Schanen and X. Li, “Transcriptional regulation of mammalian miRNA genes,” Genomics, vol. 97, no. 1, pp. 1–6, 2011. View at: Publisher Site | Google Scholar
  32. V. N. Kim, “MicroRNA biogenesis: coordinated cropping and dicing,” Nature Reviews Molecular Cell Biology, vol. 6, no. 5, pp. 376–385, 2005. View at: Publisher Site | Google Scholar
  33. A. Rodriguez, S. Griffiths-Jones, J. L. Ashurst, and A. Bradley, “Identification of mammalian microRNA host genes and transcription units,” Genome Research, vol. 14, no. 10A, pp. 1902–1910, 2004. View at: Publisher Site | Google Scholar
  34. G. M. Borchert, W. Lanier, and B. L. Davidson, “RNA polymerase III transcribes human microRNAs,” Nature Structural & Molecular Biology, vol. 13, no. 12, pp. 1097–1101, 2006. View at: Publisher Site | Google Scholar
  35. Y. Lee, K. Jeon, J.-T. Lee, S. Kim, and V. N. Kim, “MicroRNA maturation: stepwise processing and subcellular localization,” EMBO Journal, vol. 21, no. 17, pp. 4663–4670, 2002. View at: Publisher Site | Google Scholar
  36. J. Mingardi, L. Musazzi, G. De Petro, and A. Barbon, “miRNA Editing: New Insights into the Fast Control of Gene Expression in Health and Disease,” Molecular Neurobiology, vol. 55, no. 10, pp. 7717–7727, 2018. View at: Publisher Site | Google Scholar
  37. X. Cai, C. H. Hagedorn, and B. R. Cullen, “Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs,” RNA, vol. 10, no. 12, pp. 1957–1966, 2004. View at: Publisher Site | Google Scholar
  38. Y. Lee, C. Ahn, J. Han et al., “The nuclear RNase III Drosha initiates microRNA processing,” Nature, vol. 425, no. 6956, pp. 415–419, 2003. View at: Publisher Site | Google Scholar
  39. P.-W. Lau and I. J. MacRae, “The molecular machines that mediate microRNA maturation,” Journal of Cellular and Molecular Medicine, vol. 13, no. 1, pp. 54–60, 2009. View at: Publisher Site | Google Scholar
  40. R. I. Gregory, K. Yan, G. Amuthan et al., “The Microprocessor complex mediates the genesis of microRNAs,” Nature, vol. 432, no. 7014, pp. 235–240, 2004. View at: Publisher Site | Google Scholar
  41. E. Lund, S. Güttinger, A. Calado, J. E. Dahlberg, and U. Kutay, “Nuclear export of microRNA precursors,” Science, vol. 303, no. 5654, pp. 95–98, 2004. View at: Publisher Site | Google Scholar
  42. R. Yi, Y. Qin, I. G. Macara, and B. R. Cullen, “Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs,” Genes & Development, vol. 17, no. 24, pp. 3011–3016, 2003. View at: Publisher Site | Google Scholar
  43. M. Hesse and C. Arenz, “MicroRNA maturation and human disease,” Methods in Molecular Biology, vol. 1095, pp. 11–25, 2014. View at: Publisher Site | Google Scholar
  44. M. Sand, M. Skrygan, D. Georgas et al., “Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA-induced silencing complex (RISC) components argonaute-1, argonaute-2, PACT, TARBP1, and TARBP2 in epithelial skin cancer,” Molecular Carcinogenesis, vol. 51, no. 11, pp. 916–922, 2012. View at: Publisher Site | Google Scholar
  45. J. Höck and G. Meister, “The Argonaute protein family,” Genome Biology, vol. 9, no. 2, article 210, 2008. View at: Publisher Site | Google Scholar
  46. H. Wang, C. Noland, B. Siridechadilok et al., “Structural insights into RNA processing by the human RISC-loading complex,” Nature Structural & Molecular Biology, vol. 16, no. 11, pp. 1148–1153, 2009. View at: Publisher Site | Google Scholar
  47. M. A. Valencia-Sanchez, J. Liu, G. J. Hannon, and R. Parker, “Control of translation and mRNA degradation by miRNAs and siRNAs,” Genes & Development, vol. 20, no. 5, pp. 515–524, 2006. View at: Publisher Site | Google Scholar
  48. J. Brennecke, A. Stark, R. B. Russell, and S. M. Cohen, “Principles of microRNA-target recognition,” PLoS Biology, vol. 3, no. 3, p. e85, 2005. View at: Publisher Site | Google Scholar
  49. S. S. Bhat, A. Jarmolowski, and Z. Szweykowska-Kulińska, “MicroRNA biogenesis: Epigenetic modifications as another layer of complexity in the microRNA expression regulation,” Acta Biochimica Polonica, vol. 63, no. 4, pp. 717–723, 2016. View at: Publisher Site | Google Scholar
  50. D. S. Schwarz, G. Hutvágner, T. Du, Z. Xu, N. Aronin, and P. D. Zamore, “Asymmetry in the assembly of the RNAi enzyme complex,” Cell, vol. 115, no. 2, pp. 199–208, 2003. View at: Publisher Site | Google Scholar
  51. U. A. Ørom, F. C. Nielsen, and A. H. Lund, “MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation,” Molecular Cell, vol. 30, no. 4, pp. 460–471, 2008. View at: Publisher Site | Google Scholar
  52. J. I. Henke, D. Goergen, J. Zheng et al., “microRNA-122 stimulates translation of hepatitis C virus RNA,” EMBO Journal, vol. 27, no. 24, pp. 3300–3310, 2008. View at: Publisher Site | Google Scholar
  53. Y. Tay, J. Zhang, A. M. Thomson, B. Lim, and I. Rigoutsos, “MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation,” Nature, vol. 455, no. 7216, pp. 1124–1128, 2008. View at: Publisher Site | Google Scholar
  54. S. Huang, S. Wu, J. Ding et al., “MicroRNA-181a modulates gene expression of zinc finger family members by directly targeting their coding regions,” Nucleic Acids Research, vol. 38, no. 20, pp. 7211–7218, 2010. View at: Publisher Site | Google Scholar
  55. A. M. Duursma, M. Kedde, M. Schrier, C. Le Sage, and R. Agami, “miR-148 targets human DNMT3b protein coding region,” RNA, vol. 14, no. 5, pp. 872–877, 2008. View at: Publisher Site | Google Scholar
  56. S. Vasudevan, Y. Tong, and J. A. Steitz, “Switching from repression to activation: microRNAs can up-regulate translation,” Science, vol. 318, no. 5858, pp. 1931–1934, 2007. View at: Publisher Site | Google Scholar
  57. R. F. Place, L. C. Li, and D. Pookot, “MicroRNA-373 induces expression of genes with complementary promoter sequences,” in Proceedings of the National Academy of Sciences of the United States of America, vol. 105, pp. 1608–1613. View at: Publisher Site | Google Scholar
  58. J. O. Westholm and E. C. Lai, “Mirtrons: MicroRNA biogenesis via splicing,” Biochimie, vol. 93, no. 11, pp. 1897–1904, 2011. View at: Publisher Site | Google Scholar
  59. K. Miyoshi, T. Miyoshi, and H. Siomi, “Many ways to generate microRNA-like small RNAs: Non-canonical pathways for microRNA production,” Molecular Genetics and Genomics, vol. 284, no. 2, pp. 95–103, 2010. View at: Publisher Site | Google Scholar
  60. Q. Zhou, L. Yang, S. Larson et al., “Decreased miR-199 augments visceral pain in patients with IBS through translational upregulation of TRPV1,” Gut, vol. 65, no. 5, pp. 797–805, 2016. View at: Publisher Site | Google Scholar
  61. X.-J. Liao, W.-M. Mao, Q. Wang, G.-G. Yang, W.-J. Wu, and S.-X. Shao, “MicroRNA-24 inhibits serotonin reuptake transporter expression and aggravates irritable bowel syndrome,” Biochemical and Biophysical Research Communications, vol. 469, no. 2, pp. 288–293, 2016. View at: Publisher Site | Google Scholar
  62. S. Bradesi, I. Karagiannides, K. Bakirtzi et al., “Identification of spinal cord MicroRNA and gene signatures in a model of chronic stress-induced visceral hyperalgesia in rat,” PLoS One, vol. 10, no. 7, 2015. View at: Google Scholar
  63. N. H. Fourie, R. M. Peace, S. K. Abey et al., “Elevated circulating miR-150 and miR-342-3p in patients with irritable bowel syndrome,” Experimental and Molecular Pathology, vol. 96, no. 3, pp. 422–425, 2014. View at: Publisher Site | Google Scholar
  64. Q. Zhou, W. W. Souba, C. M. Croce, and G. N. Verne, “MicroRNA-29a regulates intestinal membrane permeability in patients with irritable bowel syndrome,” Gut, vol. 59, no. 6, pp. 775–784, 2010. View at: Publisher Site | Google Scholar
  65. Q. Hou, Y. Huang, S. Zhu et al., “MiR-144 Increases Intestinal Permeability in IBS-D Rats by Targeting OCLN and ZO1,” Cellular Physiology and Biochemistry, vol. 44, no. 6, pp. 2256–2268, 2018. View at: Publisher Site | Google Scholar
  66. R. O. Burney, A. E. Hamilton, L. Aghajanova et al., “MicroRNA expression profiling of eutopic secretory endometrium in women with versus without endometriosis,” Molecular Human Reproduction, vol. 15, no. 10, pp. 625–631, 2009. View at: Publisher Site | Google Scholar
  67. C. S. Kästingschäfer, S. D. Schäfer, L. Kiesel, and M. Götte, “MiR-142-3p is a novel regulator of cell viability and proinflammatory signalling in endometrial stroma cells,” Reproductive BioMedicine Online, vol. 30, no. 5, pp. 553–556, 2015. View at: Publisher Site | Google Scholar
  68. K. R. Wright, B. Mitchell, and N. Santanam, “Redox regulation of microRNAs in endometriosis-associated pain,” Redox Biology, vol. 12, pp. 956–966, 2017. View at: Publisher Site | Google Scholar
  69. A. M. Maged, W. S. Deeb, A. El Amir et al., “Diagnostic accuracy of serum miR-122 and miR-199a in women with endometriosis,” International Journal of Gynecology & Obstetrics, vol. 141, no. 1, pp. 14–19, 2018. View at: Publisher Site | Google Scholar
  70. V. S. Freire, F. C. Burkhard, T. M. Kessler, A. Kuhn, A. Draeger, and K. Monastyrskaya, “MicroRNAs may mediate the down-regulation of neurokinin-1 receptor in chronic bladder pain syndrome,” The American Journal of Pathology, vol. 176, no. 1, pp. 288–303, 2010. View at: Publisher Site | Google Scholar
  71. K. Monastyrskaya, V. Sánchez-Freire, A. Hashemi Gheinani et al., “miR-199a-5p Regulates Urothelial Permeability and May Play a Role in Bladder Pain Syndrome,” The American Journal of Pathology, vol. 182, no. 2, pp. 431–448, 2013. View at: Publisher Site | Google Scholar
  72. J. W. Lv, W. Wen, and C. Jiang, “Inhibition of microRNA-214 promotes epithelial-mesenchymal transition process and induces interstitial cystitis in postmenopausal women by upregulating Mfn2,” Experimental & Molecular Medicine, vol. 49, no. 7, 2017. View at: Google Scholar
  73. C. Jiang, Z. Tong, W. Fang et al., “Microrna-139-5p inhibits epithelial-mesenchymal transition and fibrosis in post-menopausal women with interstitial cystitis by targeting LPAR4 via the PI3K/Akt signaling pathway,” Journal of Cellular Biochemistry, vol. 119, no. 8, pp. 6429–6441, 2018. View at: Publisher Site | Google Scholar
  74. J. N. Sengupta, S. Pochiraju, P. Kannampalli et al., “MicroRNA-mediated GABA Aalpha-1 receptor subunit down-regulation in adult spinal cord following neonatal cystitis-induced chronic visceral pain in rats,” Pain, vol. 154, no. 1, pp. 59–70, 2013. View at: Google Scholar
  75. J. Zhang, J. Yu, P. Kannampalli et al., “MicroRNA-mediated downregulation of potassiumchloride-cotransporter and vesicular g-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis-induced visceral pain in rats,” PAIN, vol. 158, no. 12, pp. 2461–2474, 2017. View at: Publisher Site | Google Scholar
  76. J. Zhao, M.-C. Lee, A. Momin et al., “Small RNAs control sodium channel expression, nociceptor excitability, and pain thresholds,” The Journal of Neuroscience, vol. 30, no. 32, pp. 10860–10871, 2010. View at: Publisher Site | Google Scholar
  77. G. F. Longstreth, W. G. Thompson, W. D. Chey, L. A. Houghton, F. Mearin, and R. C. Spiller, “Functional bowel disorders,” Gastroenterology, vol. 130, no. 5, pp. 1480–1491, 2006. View at: Publisher Site | Google Scholar
  78. S. Nusrat and P. B. Miner, “New pharmacological treatment options for irritable bowel syndrome with constipation,” Expert Opinion on Emerging Drugs, vol. 20, no. 4, pp. 625–636, 2015. View at: Publisher Site | Google Scholar
  79. M. Furnari, N. De Bortoli, I. Martinucci et al., “Optimal management of constipation associated with irritable bowel syndrome,” Therapeutics and Clinical Risk Management, vol. 11, pp. 691–703, 2015. View at: Google Scholar
  80. K. Bradford, W. Shih, E. J. Videlock et al., “Association Between Early Adverse Life Events and Irritable Bowel Syndrome,” Clinical Gastroenterology and Hepatology, vol. 10, no. 4, pp. 385–390, 2012. View at: Publisher Site | Google Scholar
  81. C. S. North, B. A. Hong, and D. H. Alpers, “Relationship of functional gastrointestinal disorders and psychiatric disorders: Implications for treatment,” World Journal of Gastroenterology, vol. 13, no. 14, pp. 2020–2027, 2007. View at: Publisher Site | Google Scholar
  82. R. M. Van den Wijngaard, O. I. Stanisor, S. A. van Diest et al., “Susceptibility to stress induced visceral hypersensitivity in maternally separated rats is transferred across generations,” Neurogastroenterology & Motility, vol. 25, no. 12, pp. e780–e790, 2013. View at: Publisher Site | Google Scholar
  83. Y. A. Saito and N. J. Talley, “Genetics of irritable bowel syndrome,” American Journal of Gastroenterology, vol. 103, no. 8, pp. 2100–2104, 2008. View at: Publisher Site | Google Scholar
  84. D. A. Drossman and W. L. Hasler, “Rome IV—functional GI disorders: disorders of gut-brain interaction,” Gastroenterology, vol. 150, no. 6, pp. 1257–1261, 2016. View at: Publisher Site | Google Scholar
  85. J. Chen, H. Pan, T. P. Rothman, P. R. Wade, and M. D. Gershon, “Guinea pig 5-HT transporter: cloning, expression, distribution, and function in intestinal sensory reception,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 275, no. 3, pp. G433–G448, 1998. View at: Publisher Site | Google Scholar
  86. R. D. Blakely, H. E. Berson, R. T. Fremeau Jr. et al., “Cloning and expression of a functional serotonin transporter from rat brain,” Nature, vol. 354, no. 6348, pp. 66–70, 1991. View at: Publisher Site | Google Scholar
  87. S. Bradesi, V. Golovatscka, H. S. Ennes et al., “Role of astrocytes and altered regulation of spinal glutamatergic neurotransmission in stress-induced visceral hyperalgesia in rats,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 301, no. 3, pp. G580–G589, 2011. View at: Publisher Site | Google Scholar
  88. J. Wu, S. H. Cui, and H. Z. Li, “Ultrasound diagnosis in gynecological acute abdomen,” Journal of Biological Regulators and Homeostatic Agents, vol. 30, no. 1, pp. 211–217, 2017. View at: Google Scholar
  89. J. L. Pope, A. A. Bhat, A. Sharma et al., “Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling,” Gut, vol. 63, pp. 622–634, 2014. View at: Publisher Site | Google Scholar
  90. C. Lunardi, C. Bason, M. Dolcino et al., “Antiflagellin antibodies recognize the autoantigens Toll-Like Receptor 5 and Pals 1-associated tight junction protein and induce monocytes activation and increased intestinal permeability in Crohn's disease,” Journal of Internal Medicine, vol. 265, no. 2, pp. 250–265, 2009. View at: Publisher Site | Google Scholar
  91. S. Govatati, N. K. Tangudu, M. Deenadayal, B. Chakravarty, S. Shivaji, and M. Bhanoori, “Association of E-cadherin single nucleotide polymorphisms with the increased risk of endometriosisin Indian women,” Molecular Human Reproduction, vol. 18, no. 5, Article ID gar079, pp. 280–287, 2012. View at: Publisher Site | Google Scholar
  92. L. Santoro, S. Campo, F. D’Onofrio et al., “Looking for Celiac Disease in Italian Women with Endometriosis: A Case Control Study,” BioMed Research International, vol. 2014, Article ID 236821, 2014. View at: Publisher Site | Google Scholar
  93. R. N. Taylor, L. Hummelshoj, P. Stratton, and P. Vercellini, “Pain and endometriosis: Etiology, impact, and therapeutics,” Middle East Fertility Society Journal, vol. 17, no. 4, pp. 221–225, 2012. View at: Publisher Site | Google Scholar
  94. A. D. Greene, S. A. Lang, J. A. Kendziorski, J. M. Sroga-Rios, T. J. Herzog, and K. A. Burns, “Endometriosis: Where are we and where are we going?” Reproduction, vol. 152, no. 3, pp. R63–R78, 2016. View at: Publisher Site | Google Scholar
  95. Z. Liang, Y. Chen, Y. Zhao et al., “miR-200c suppresses endometriosis by targeting MALAT1 in vitro and in vivo,” Stem Cell Research & Therapy, vol. 8, no. 1, 2017. View at: Publisher Site | Google Scholar
  96. S. K. Kavoussi, C. S. Lim, B. D. Skinner, D. I. Lebovic, and S. As-Sanie, “New paradigms in the diagnosis and management of endometriosis,” Current Opinion in Obstetrics and Gynecology, vol. 28, no. 4, pp. 267–276, 2016. View at: Publisher Site | Google Scholar
  97. A. V. Jones, J. R. F. Hockley, C. Hyde et al., “Genome-wide association analysis of pain severity in dysmenorrhea identifies association at chromosome 1p13.2, near the nerve growth factor locus,” PAIN, vol. 157, no. 11, pp. 2571–2581, 2016. View at: Publisher Site | Google Scholar
  98. B. P. Ciszek, A. A. Khan, H. Dang et al., “MicroRNA expression profiles differentiate chronic pain condition subtypes,” Translational Research, vol. 166, no. 6, pp. 706–720.e11, 2015. View at: Publisher Site | Google Scholar
  99. Y.-T. Chen, H.-J. Chiang, C.-H. Chen et al., “Melatonin treatment further improves adipose-derived mesenchymal stem cell therapy for acute interstitial cystitis in rat,” Journal of Pineal Research, vol. 57, no. 3, pp. 248–261, 2014. View at: Publisher Site | Google Scholar
  100. A. H. Gheinani, F. C. Burkhard, and K. Monastyrskaya, “Deciphering microRNA code in pain and inflammation: Lessons from bladder pain syndrome,” Cellular and Molecular Life Sciences, vol. 70, no. 20, pp. 3773–3789, 2013. View at: Publisher Site | Google Scholar
  101. P. Kannampalli, R. Babygirija, J. Zhang et al., “Neonatal bladder inflammation induces long-term visceral pain and altered responses of spinal neurons in adult rats,” Neuroscience, vol. 346, pp. 349–364, 2017. View at: Publisher Site | Google Scholar
  102. K. A. Moore, T. Kohno, L. A. Karchewski, J. Scholz, H. Baba, and C. J. Woolf, “Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord,” The Journal of Neuroscience, vol. 22, no. 15, pp. 6724–6731, 2002. View at: Publisher Site | Google Scholar
  103. D. Schoffnegger, B. Heinke, C. Sommer, and J. Sandkühler, “Physiological properties of spinal lamina II GABAergic neurons in mice following peripheral nerve injury,” The Journal of Physiology, vol. 577, no. 3, pp. 869–878, 2006. View at: Publisher Site | Google Scholar
  104. J. Knabl, R. Witschi, K. Hösl et al., “Reversal of pathological pain through specific spinal GABAA receptor subtypes,” Nature, vol. 451, no. 7176, pp. 330–334, 2008. View at: Publisher Site | Google Scholar
  105. Y. D’Alessandra, M. C. Carena, L. Spazzafumo et al., “Diagnostic potential of plasmatic microRNA signatures in stable and unstable angina,” PLoS One, vol. 8, no. 11, 2013. View at: Publisher Site | Google Scholar
  106. A. Pleister, H. Selemon, S. M. Elton, and T. S. Elton, “Circulating miRNAs: Novel biomarkers of acute coronary syndrome?” Biomarkers in Medicine, vol. 7, no. 2, pp. 287–305, 2013. View at: Publisher Site | Google Scholar
  107. T. Reichlin, W. Hochholzer, S. Bassetti et al., “Early diagnosis of myocardial infarction with sensitive cardiac troponin assays,” The New England Journal of Medicine, vol. 361, no. 9, pp. 858–867, 2009. View at: Publisher Site | Google Scholar
  108. T. Keller, T. Zeller, D. Peetz et al., “Sensitive troponin I assay in early diagnosis of acute myocardial infarction,” The New England Journal of Medicine, vol. 361, no. 9, pp. 868–877, 2009. View at: Publisher Site | Google Scholar
  109. Y. Devaux, M. Vausort, and E. Goretti, “Use of circulating microRNAs to diagnose acute myocardial infarction,” Clinical Chemistry, vol. 58, no. 3, pp. 559–567, 2012. View at: Publisher Site | Google Scholar
  110. J. Ren, J. Zhang, N. Xu et al., “Signature of circulating MicroRNAs as potential biomarkers in vulnerable coronary artery disease,” PLoS ONE, vol. 8, no. 12, Article ID e80738, 2013. View at: Publisher Site | Google Scholar
  111. T. Zeller, T. Keller, F. Ojeda et al., “Assessment of microRNAs in patients with unstable angina pectoris,” European Heart Journal, vol. 35, no. 31, pp. 2106–2114, 2014. View at: Publisher Site | Google Scholar
  112. L. Zhang, X. Chen, and T. Su, “Circulating miR-499 are novel and sensitive biomarker of acute myocardial infarction,” Journal of Thoracic Disease, vol. 7, no. 3, pp. 303–308, 2015. View at: Google Scholar
  113. X. Li, Y. Yang, L. Wang et al., “Plasma miR-122 and miR-3149 Potentially Novel Biomarkers for Acute Coronary Syndrome,” PLoS ONE, vol. 10, no. 5, 2015. View at: Publisher Site | Google Scholar
  114. X. Chen, L. Zhang, and T. Su, “Kinetics of plasma microRNA-499 expression in acute myocardial infarction,” Journal of Thoracic Disease, vol. 7, no. 5, pp. 890–896, 2015. View at: Google Scholar
  115. E. Coskunpinar, H. A. Cakmak, A. K. Kalkan, N. O. Tiryakioglu, M. Erturk, and Z. Ongen, “Circulating miR-221-3p as a novel marker for early prediction of acute myocardial infarction,” Gene, vol. 592, no. 1, pp. 90–96, 2016. View at: Publisher Site | Google Scholar
  116. S. M. Shalaby, A. S. El-Shal, A. Shoukry, M. H. Khedr, and N. Abdelraheim, “Serum miRNA-499 and miRNA-210: A potential role in early diagnosis of acute coronary syndrome,” IUBMB Life, pp. 673–682, 2016. View at: Publisher Site | Google Scholar
  117. M. Zhang, Y.-J. Cheng, J. D. S. Sara et al., “Circulating microRNA-145 is associated with acute myocardial infarction and heart failure,” Chinese Medical Journal, vol. 130, no. 1, pp. 51–56, 2017. View at: Publisher Site | Google Scholar
  118. R. Bai, Q. Yang, R. Xi, L. Li, D. Shi, and K. Chen, “miR-941 as a promising biomarker for acute coronary syndrome,” BMC Cardiovascular Disorders, vol. 17, no. 1, p. 227, 2017. View at: Google Scholar
  119. Y. Cui, J. Song, S. Li, C. Lee, F. Zhang, and H. Chen, “Plasmatic microRNA signatures in elderly people with stable and unstable angina,” International Heart Journal, vol. 59, no. 1, pp. 43–50, 2018. View at: Publisher Site | Google Scholar

Copyright © 2018 Zhuo-Ying Tao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

735 Views | 270 Downloads | 2 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.