Dynamic Changes in the MicroRNA Expression Profile Reveal Multiple Regulatory Mechanisms in the Spinal Nerve Ligation Model of Neuropathic Pain

Schack, David von; Agostino, Michael; Murray, B. Stuart; Li, Yizheng; Reddy, Padmalatha S.; Jin, Chen; Choe, Sung; Strassle, Brian W.; Li, Christine; Bates, Brian; Zhang, Lynn; Hu, Huijuan; Kotnis, Smita; Bingham, Brendan; Liu, Wei; Whiteside, Garth T.; Samad, Tarek A.; Kennedy, Jeffrey D.; Ajit, Seena K.

doi:10.1371/journal.pone.0017670

Cited by 132 publications

(115 citation statements)

References 56 publications

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“…Target prediction algorithms use different parameters to provide candidate target genes for miRNAs. Some of the miRNAs are of special interest concerning their putative targets, so TargetScan was used to identify putative targets and to provide a foundation for functional analyses of neuropathic pain as done in previous reports [42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Circulating microRNA expression profile: a novel potential predictor for chronic nervous lesions

Xu¹,

Zhang²,

Pu³

et al. 2014

ABBS

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The mechanisms of chronic neuropathic pain are not clear. Serum microRNAs (miRNAs) might show a special feature for chronic nervous lesions. However, little is known about the changes in circulating miRNAs for the neuropathic pain. Therefore, changes in the circulating miRNAs expression profile for the neuropathic pain were investigated. Serum was collected from rats before and after spinal nerve ligation (SNL) surgery, and a microarray analysis was performed to determine the changes in miRNA expression profile. The expression of inflammatory cytokines in serum from the same individuals, including interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), and monocyte chemotactic protein-1 (MCP-1), was also measured. The results showed that the expression levels of IL-6, TNF-a, and MCP-1 were significantly elevated in SNL rats which were significantly correlated with pain levels. Nine miRNAs with significantly different expression levels before and after SNL surgery were identified by microarray analysis, which were further validated by quantitative real-time polymerase chain reaction analyses. Compared with naive rats without SNL surgery, the expression of five miRNAs (hsa-miR-221, hsa-miR-34c, hsa-miR-21, hsa-miR-30a-5p, and hsa-miR-206) in the serum of rats after SNL surgery was decreased and four miRNAs (hsa-miR-31-5p, hsa-miR-133b, hsamiR-22, and hsa-miRPlus-A1087) were increased, suggesting that miRNA changes may involve in the regulation of neuropathic pain. TargetScan was used to predict mRNA targets for these miRNAs, and the results showed that the transcripts with multiple predicted target sites belonged to neurologically important pathways. Bioinformatics analysis revealed that several target genes are related to the activation of cell signaling associated with nervous lesions. In this study, the changes to miRNA profiles in serum under neuropathic pain conditions were shown for the first time, suggesting that circulating miRNAs profile in serum is a potential predictor for neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

Circulating microRNA expression profile: a novel potential predictor for chronic nervous lesions

Xu¹,

Zhang²,

Pu³

et al. 2014

ABBS

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“…miRNAs are a large class of short non-coding RNAs (~22 nt long), many of which are expressed either predominantly or exclusively in the nervous system (14)(15)(16)(17)(18)(19)(20)(21). Furthermore, changes (either increases or decreases) in miRNA expression have been found in many disease states (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Differential expression of miRNAs in the nervous system of a rat model of bilateral sciatic nerve chronic constriction injury

Shen

et al. 2013

International Journal of Molecular Medicine

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Abstract. Chronic neuropathic pain is associated with global changes in gene expression in different areas of the nociceptive pathway. MicroRNAs (miRNAs) are small (~22 nt long) noncoding RNAs, which are able to regulate hundreds of different genes post-transcriptionally. The aim of this study was to determine the miRNA expression patterns in the different regions of the pain transmission pathway using a rat model of human neuropathic pain induced by bilateral sciatic nerve chronic constriction injury (bCCI). Using microarray analysis and quantitative reverse transcriptase-PCR, we observed a significant upregulation in miR-341 expression in the dorsal root ganglion (DRG), but not in the spinal dorsal horn (SDH), hippocampus or anterior cingulate cortex (ACC), in the rats with neuropathic pain compared to rats in the naïve and sham-operated groups. By contrast, the expression of miR-203, miR-181a-1 * and miR-541 * was significantly reduced in the SDH of rats with neuropathic pain. Our data indicate that miR-341 is upregulated in the DRG, whereas miR-203, miR-181a-1 * and miR-541 * are downregulated in the SDH under neuropathic pain conditions. Thus, the differential expression of miRNAs in the nervous system may play a role in the development of chronic pain. These observations may aid in the development of novel treatment methods for neuropathic pain, which may involve miRNA gene therapy in local regions. IntroductionNeuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting either the peripheral or central nervous system (1,2). Although pain has been investigated in depth for decades, neuropathic pain is still frequently under-treated (3), due to poor understanding of its pathophysiological and molecular mechanisms. Several regions of the nociceptive pathway, including the anterior cingulate cortex (ACC), hippocampus, spinal dorsal horn (SDH) and dorsal root ganglion (DRG), are involved in the development and maintenance of neuropathic pain (4-9). Several recent studies have shown that peripheral and central sensitization are associated with global changes in gene expression in different regions of the pain transmission pathway, and that these changes may be part of the mechanisms behind neuropathic pain (10-13). In order to elucidate the molecular mechanisms underlying neuropathic pain, it is essential to determine how gene expression patterns are altered by nerve injuries and how these alterations lead to the development and maintenance of chronic pain.miRNAs are a large class of short non-coding RNAs (~22 nt long), many of which are expressed either predominantly or exclusively in the nervous system (14-21). Furthermore, changes (either increases or decreases) in miRNA expression have been found in many disease states (22-24). Bilateral sciatic nerve chronic constriction injury (bCCI) is commonly used as a model for studying human neuropathic pain, in which chromic gut sutures are used to ligate each sciatic nerve. This model is characterized by long-lasting cold all...

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“…It should be pointed out that the differences found across different pain models suggest the existence of disorder specific miRNAs rather than common miRNA regulators of nociceptive modulation. For example, members of the miR-34 family are strongly underexpressed following neuropathic pain induction while appears highly overexpressed following bone metastatic pain induction in DRG [85,86]. Also, it has been described that the interactions between sensory neurons and non-neuronal cells such as immune cells and microglia modulate nociceptive sensitivity [87] and therefore changes in other cells of the body, such as blood cells, might be indicators of individual changes in nociceptive thresholds, even if the alteration pattern of the deregulated microRNAs does not match with that in the tissue affected they might still serve as reporters.…”

Section: Mt Impact On the Nervous System And On Pain Reliefmentioning

confidence: 99%

Unraveling molecular determinants of manual therapy: an approach to integrative therapeutics for the treatment of fibromyalgia and CFS/ME

Espejo¹,

García-Escudero²,

Oltra³

2018

Preprint

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Abstract:Application of protocols without parameter standardization and rigorous controls has led manual therapy (MT) and other physiotherapy approaches to controversial outcomes. Thus, there is an urgency to carefully define standard protocols that elevate physiotherapy treatments to rigorous scientific demands. One way this can be achieved is by studying gene expression and additional physiological changes that associate to particular, parameter-controlled, treatments in animal models and translating this knowledge to properly design objective, quantitatively-monitored clinical trials. Here, we propose a Molecular Physiotherapy Approach (MPTA), requiring multidisciplinary teams, to uncover the scientific reasons behind the numerous reports of MT that historically attribute benefits to these treatments. The review focuses in the identification of MT-induced physiological and molecular responses that could be used for the treatment of fibromyalgia (FM) and CFS/ME. The systemic effect associated to mechanical-load responses is considered of particular relevance as it suggests that defined, low-pain areas could be selected for treatments with overall benefits, an aspect that might result essential to treat FM. Additionally, MT can provide muscle conditioning to sedentary patients without demanding strenuous physical effort, detrimental for CFS/ME patients, placing MT as a real option for integrative medicine programs to treat FM and CFS/ME.

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Dynamic Changes in the MicroRNA Expression Profile Reveal Multiple Regulatory Mechanisms in the Spinal Nerve Ligation Model of Neuropathic Pain

Cited by 132 publications

References 56 publications

Circulating microRNA expression profile: a novel potential predictor for chronic nervous lesions

Circulating microRNA expression profile: a novel potential predictor for chronic nervous lesions

Differential expression of miRNAs in the nervous system of a rat model of bilateral sciatic nerve chronic constriction injury

Unraveling molecular determinants of manual therapy: an approach to integrative therapeutics for the treatment of fibromyalgia and CFS/ME

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