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

Abstract

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...

Decreased MicroRNA-125a-3p Contributes to Upregulation of p38 MAPK in Rat Trigeminal Ganglions with Orofacial Inflammatory Pain

“…[13] reported spinal miR-146a and -183 cluster expression in osteoarthritic pain of knee joints. Besides, other studies reported the differential expressions of miRNAs in animal models with chronic neuropathic pain induced by lumbar nerve injury at peripheral and central nerve system level [10], [12], [15]. However, there were limited studies reported in the orofacial region.…”

Role of MicroRNA in Visceral Pain

“…90 In the neuropathic pain models, a downregulation of miR-181a or other members of the miR-181 family, namely miR-181b/c/d has been documented. 91,92 In this context, deregulation of miR-181a expression in various brain regions has been reported following chronic exposure to drug of abuse.…”

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

“…An up regulation of miR-341 in the DRG and down regulation of miR-203, miR-181a-1 and miR-541 in the spinal dorsal horn leads to development of neuropathic pain [29]. Continually, a sciatic nerve ligation (SNL) study shows a drastic decrease in miR200b and miR429 in NAcc neurons [67].…”

“…In animal models, the dorsal root ganglia, the spinal dorsal horn, and the brain are all areas of miRNA modulation [28]. Following injury, the differential expression of miRNAs in the nervous system may play a role in predicting the development of chronic pain [29]. CED has not been explored extensively as a delivery method for miRNAs in the treatment of NP, recent studies have identified several microRNAs including miR-21, miR-486, miR-20 involved in key mechanisms of SCI such as cell death or astrogliosis, direct evidence on the role of miRNAs in SCI is scarce [30].…”

“…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 [29]. The evidence for nerve injury-induced change by noxious stimuli in expression of miRNAs and Kcna2 antisense RNA in the dorsal root ganglion and its implication in neuropathic pain is discussed [81].…”