Changes in expression of sensory organ-specific microRNAs in rat dorsal root ganglia in association with mechanical hypersensitivity induced by spinal nerve ligation

Abstract

Chronic neuropathic pain caused by peripheral nerve injury is associated with global changes in gene expression in damaged neurons. To understand the molecular mechanisms underlying neuropathic pain, it is essential to elucidate how nerve injury alters gene expression and how the change contributes to the development and maintenance of chronic pain. MicroRNAs are non-protein-coding RNA molecules that regulate gene expression in a wide variety of biological processes mainly at the level of translation. This study investigated the possible involvement of microRNAs in gene regulation relevant to neuropathic pain. The analyses focused on a sensory organ-specific cluster of microRNAs that includes miR-96, -182, and -183. RT-PCR analyses confirmed that these microRNAs were highly enriched in the dorsal root ganglion (DRG) of adult rats. Using the L5 spinal nerve ligation (SNL) model of chronic neuropathic pain, we observed a significant reduction in expression of these microRNAs in injured DRG neurons compared to controls. In situ hybridization and immunohistochemical analyses revealed that these microRNAs are expressed in both myelinated (N52 positive) and unmyelinated (IB4 positive) primary afferent neurons. They also revealed that the intracellular distributions of the microRNAs in DRG neurons were dramatically altered in animals with mechanical hypersensitivity. Whereas microRNAs were uniformly distributed within the DRG soma of non-allodynic animals, they were preferentially localized to the periphery of neurons in allodynic animals. The redistribution of microRNAs was associated with changes in the distribution of the stress granule protein TIA-1. These data demonstrate that SNL induces changes in expression levels and patterns of miR-96, -182, and -183, implying their possible contribution to chronic neuropathic pain through translational regulation of pain-relevant genes. Moreover, stress granules were suggested to be assembled and associated with microRNAs after SNL, which may play a role in modification of microRNA-mediated gene regulation in DRG neurons.

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

“…These changes appear to be the result of the specific regulation of miRNAs in individual tissues or organs along the pain transmission pathway, rather than a global change in miRNA or small RNA levels, as the miRNA changes observed after the induction of bCCI were unique to their specific region. Previous studies have determined that miRNA expression in the nociceptive system is not only temporally and spatially specific, but also stimulus-dependent (14,22). However, to our knowledge, little is known about the differential expression of miRNAs in the nociceptive pathway during bCCI, and our is the first study to investigate this.…”

“…Aberrant miRNA expression has also been linked to a variety of diseases, including several nervous system diseases (32)(33)(34). For example, miR-219 modulates N-methyl-D-aspartate (NMDA) receptor-mediated neurobehavioral dysfunction, which is implicated in schizophrenia and autism (35), and the expression of the sensory organ-specific miR-183 family has been shown to be altered following spinal nerve ligation (14). Moreover, Table I.…”

“…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).…”

Identification and quantitative analyses of microRNAs located in the distal axons of sympathetic neurons

“…This method has been successfully employed in the quantitative analyses of miRNA expression by realtime PCR (Saba et al 2008;Aldrich et al 2009;Hébert et al 2009). Briefly, DC T values for each miRNA were obtained after normalizing to U6 snRNA, a common normalizer for miRNA expression, and miR-103, which has been previously shown to be a very stable reference miRNA (Peltier and Latham 2008).…”

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

“…Neuropathic pain decreased with miR23b infusion that occurs as result of the NOX4 gene inactivated, where MiR23b protects GABAergic neurons against ROS/p38/c-JNK apoptotic cell death [61].A mouse model that utilized NOX4 and miR23b revealed both negative and positive impacts on neuropathic pain. Continually, Spinal nerve ligation (SNL) alters expression levels of miR-96, miR-182, and miR-183, suggesting that these molecules related to chronic neuropathic pain through translational regulation of painrelevant genes [62]. MiRNAs are involved in the post-transcriptional regulation of hundreds of genes and their relationship to chronic pain accompanied by significant changes in gene expression in various types of cells [63].…”