Differential expression of microRNAs in mouse pain models
© Kusuda et al; licensee BioMed Central Ltd. 2011
Received: 18 August 2010
Accepted: 7 March 2011
Published: 7 March 2011
MicroRNAs (miRNAs) are short non-coding RNAs that inhibit translation of target genes by binding to their mRNAs. The expression of numerous brain-specific miRNAs with a high degree of temporal and spatial specificity suggests that miRNAs play an important role in gene regulation in health and disease. Here we investigate the time course gene expression profile of miR-1, -16, and -206 in mouse dorsal root ganglion (DRG), and spinal cord dorsal horn under inflammatory and neuropathic pain conditions as well as following acute noxious stimulation.
Quantitative real-time polymerase chain reaction analyses showed that the mature form of miR-1, -16 and -206, is expressed in DRG and the dorsal horn of the spinal cord. Moreover, CFA-induced inflammation significantly reduced miRs-1 and -16 expression in DRG whereas miR-206 was downregulated in a time dependent manner. Conversely, in the spinal dorsal horn all three miRNAs monitored were upregulated. After sciatic nerve partial ligation, miR-1 and -206 were downregulated in DRG with no change in the spinal dorsal horn. On the other hand, axotomy increases the relative expression of miR-1, -16, and 206 in a time-dependent fashion while in the dorsal horn there was a significant downregulation of miR-1. Acute noxious stimulation with capsaicin also increased the expression of miR-1 and -16 in DRG cells but, on the other hand, in the spinal dorsal horn only a high dose of capsaicin was able to downregulate miR-206 expression.
Our results indicate that miRNAs may participate in the regulatory mechanisms of genes associated with the pathophysiology of chronic pain as well as the nociceptive processing following acute noxious stimulation. We found substantial evidence that miRNAs are differentially regulated in DRG and the dorsal horn of the spinal cord under different pain states. Therefore, miRNA expression in the nociceptive system shows not only temporal and spatial specificity but is also stimulus-dependent.
MicroRNAs (miRNAs) are endogenously expressed short non-coding RNAs thought to inhibit protein translation through binding to a target complementary mRNA [1–6]. Thus, the encoded genetic information is not only transcribed and translated into proteins but also regulates these processes through miRNA sequence-guided interactions with the related miRNA [2, 7–9]. Expression analysis of miRNAs has been widely used to monitor tissue-specific miRNA expression and regulatory changes in developmental stages, cell types and tissues [1, 10, 11]. Tissue and temporal specificity suggest that miRNAs sequences have an organ and/or cell type-specific function [12–16]. Furthermore, abnormal patterns of miRNA expression have also been found in many disease states where both increased and decreased expression of miRNAs have been described [16, 17]. The first experimental reports addressing the involvement of miRNAs in the nociceptive system clearly indicate that inflammatory muscle pain , and peripheral nerve injury  modify the expression profile of a number of miRNAs in trigeminal and dorsal root ganglion, respectively. A recent work provided evidence that miRNAs regulate the expression of several transcripts associated with inflammatory pain . Indeed, the nociceptive system is substantially modified in response to tissue damage, inflammation or injury to the nervous system where changes in gene expression patterns are a marked molecular mechanism underlying the development and maintenance of chronic pain [21–25]. Hence, transcriptional changes can dramatically alter the phenotypic profile and function of neurons and glia cells in the dorsal root ganglion and spinal cord dorsal horn, where nociceptive messages are primarily released to the central nervous system [21, 22]. However, our understanding on the mechanisms regulating post-transcriptional machinery remains very limited. In the present study we tested the hypothesis that in addition to temporal or spatial-specificity miRNA expression is also stimulus-dependent in the nociceptive system. In the present study the criteria to select four miRNAs were their reported expression in the mouse nervous system [10, 26] and/or their predicted pain-related target genes, such as brain-derived neurotrophic factor, mitogen activated protein kinase, phospholipase A2, and opioid receptor from in silico investigation [27, 28]. Therefore, we investigated the temporal, spatial and stimulus-dependent specificity of miRNAs by monitoring the time-course expression of miR-1, miR-16, miR-122a, and miR-206 in mouse DRG and spinal cord dorsal horn under inflammatory and neuropathic pain states as well as after acute nociceptive stimulation.
Adult Balb/c mice (20-25 g) were housed 4-5 per cage on a 12 hours light/dark cycles (lights on at 6 A.M.) and kept at 25°C ± 1°C. Food and water were available ad libitum. Behavioral experiments were performed between 9 A.M. and 4 P.M. The experimental procedures performed on animals were approved by the Ethical Committee for Animal Experimentation of Ribeirão Preto School of Medicine, University of São Paulo and followed the International Association for the Study of Pain guidelines for investigations of experimental pain in conscious animals .
Chronic inflammatory pain model
Tissue inflammation was produced by injecting 20 μL of CFA-complete Freund's adjuvant (Sigma, St. Louis, MO) subcutaneously in the dorsal aspect of the left hind-paw whereas mineral oil (Sigma) was used as control. Paw withdrawal thresholds to mechanical stimuli were assessed 12 h, 1, 3 and 7 days post-injection. At the completion of behavioral testing, mice were euthanized. Control animals were euthanized 12 h post-injection.
Neuropathic pain model
Nerve injury was performed in anesthetized mice (ketamine and xylazine, 60 and 8 mg/kg, respectively) by tying a tight ligature with 8-0 silk wire around approximately one-third to one-half of the diameter of the left sciatic nerve . Sham-operated animals had the left sciatic nerve exposed, but not ligated. After surgery nerve-injured animals were randomly separated in 4 groups and the development of tactile stimulus-induced neuropathic pain hypersensitivity was assessed at 1, 3, 7 and 14 days post-injury. By the end of the behavioral assay, mice were euthanized. Sham-operated control animals were euthanized 12 h post-injection.
Animals were anesthetized with ketamine (60 mg/kg) and xylazine (8 mg/kg), and had the left sciatic nerve transected. A segment of approximately 1 mm was removed and the stumps were tightly ligated with 8-0 silk wire. Sham-operated animals had the sciatic nerve exposed but not sectioned. Nerve-injuried animals were separated in 3 groups and euthanized 1, 3, and 7 days post-lesion. Sham-operated animals were killed 24 hours after surgery. The left L4-L5 DRG and lumbar spinal dorsal horn were harvested immediately after euthanasia and processed for total RNA extraction.
Acute noxious stimulation
Acute pain was induced by subcutaneous injection of capsaicin in the dorsal aspect of the left hindpaw. Two doses of capsaicin were tested, 2 and 10 μg/20 μL. Control animals were injected with vehicle (89.5% saline, 10% ethanol, 0.5% Tween-80). Animals were euthanized 10 minutes post injection and DRG and the lumbar spinal cord dorsal horn dissected out for RNA extraction.
Mechanical hypersensitivity was assessed before and after the injection of CFA or nerve injury by measuring the paw withdrawal threshold in response to probing calibrated Semmes-Weinstein monofilaments (von Frey hairs; Stoelting, Wood Dale, IL). Animals were placed on an elevated meshed grid which allowed full access to the ventral aspect of the hindpaws. A logarithmic series of 9 filaments were applied to the left hindpaw to determine the threshold stiffness required for 50% paw withdrawal according to the non-parametric method of Dixon  as described by Chaplan et al. . This behavioral analysis ensured that all animals selected to the miRNA expression assay developed mechanical hypersensitivity over the entire period of investigation in the inflammatory and neuropathic pain models. In the acute pain model, nocifensive behavior was monitored as time spent biting/licking capsaicin or vehicle-injected paw for 10 min.
Animals were euthanized by cervical dislocation and the left DRG (L4-L5) as well as the lumbar (L4-L6) spinal cord were dissected out. Next, the spinal cord was further dissected in PBS (4°C) by removing only the left superior quadrant of the spinal cord. Then, the tissues were rapidly homogenized in Trizol reagent at 4°C and frozen at -80°C for further processing.
Multiplexing reverse transcriptase reaction
Total RNA from DRG and the dorsal horn of the spinal cord was isolated using Trizol® reagent (Invitrogen) according to the manufacture's instruction. RNA quality and quantity were assessed using a spectrophotometer (Eppendorf BioPhotometer plus). For multiplexing reverse transcriptase reactions we used TaqMan microRNA Reverse Transcription kit with specific primers for miR-1, -16, -122a, -206, and snoR-202 following protocol provided by the manufacture (Applied Biosystems).
To quantify miRNAs by real-time RT- PCR we used TaqMan® Universal PCR Master Mix, No AmpErase® UNG (Applied Biosystems). Amplification was performed according to the manufacture's standard protocol. PCR primers and probes for amplification of the mouse mature miRNAs were specifically design for miR-1, -16, -122a, -206, and snoR-202 (Applied Biosystems). RT-PCR analysis was performed on an ABI5500HT instrument (ABI Inc.). All reactions were run in duplicate. The relative quantity of each miRNA in the tissues was calculated using the equation RQ = 2-ΔΔCT . SnoR-202 was measured by the same method and remained stable along the tested time period (data not shown). Therefore, snoR-202 was used for normalization as the internal control gene whereas the calibrator was the mean threshold cycle (C T) value for each control group associated with their respective pain model.
Pain-related target genes predicted for miR-1, -16, -122, and -206 from in silico analysis.
1, 16, 122, 206
12.6, 13.9, x, 8.7
x, x, 15.9, x
-0.23, x, x, -0.23
1, 16, 122
x, 5.9, x
x, x, 15.5
-0.21, x, x
1, 122, 206
5.6, 3.3, 6.6
-0.20, x, x
-0.06, x, -0.06
We have also addressed the question whether miRNAs expression would be influenced by acute nociceptive stimulation. Bai and collaborators have shown a significant down-regulation of a number of miRNAs as early as 30 min after CFA injection . We challenge this short-time effect on miRNA expression by injecting capsaicin into the dorsal aspect of the mouse hind paw. Capsaicin immediately depolarizes primary afferent sensory neurons through the transient receptor potential vanilloid type-1, a non-selective cation channel . Interestingly, 10 min after capsaicin injection miR-1 and -16 were up-regulated in DRG. A possible mechanism underlying this phenomenon might involve regulation of immediate-early genes (IEGs), such as c-fos, c-jun and c-myc. These genes show rapid and transient expression in the absence of de novo protein synthesis [42–44]. In particular, c-fos, which is expressed at low levels in the intact brain under basal conditions, is stereotypically induced in response to several extracellular signals, including ions, neurotransmitters, growth factors and drugs [45–47]. It is widely accepted that regulatory IEGs are involved in the stimulus-transcription coupling where c-fos has been considered a generic marker of neuronal depolarization [48–51]. C-Fos protein forms transcriptionally active dimmers with members of the c-jun family, referred to as AP-1 transcription factor. Recent data have associated miRNA activity with Fos mRNA, inhibiting Fos translation . Given the importance of AP-1 as potent transcriptional activator, it is reasonable to speculate that various mechanisms would have evolved to regulate its activity, including miRNA activity. We were also interested in investigating whether miRNA expression would be dependent on stimulus intensity. Behaviorally, capsaicin administration induces a pronounced nocifensive response in a concentration-dependent manner. However, the enhanced miRNA expression in DRG did not show any association between stimulus intensity and expression pattern suggesting a ceiling effect. Conversely, in the spinal dorsal horn 10 μg, but not 2 μg, of capsaicin induced a significant downregulation of miR-206 indicating that miRNAs may also be activated in a stimulus intensity-dependent fashion.
In summary, our data shows that miRNAs are differentially regulated under chronic and acute pain states. We speculate that miRNAs may be involved in the mechanisms underlying different pain conditions by fine-tuning the expression of pro and/or antinociceptive molecules. Whether these miRNAs activity is associated with the mechanisms underlying inflammatory and neuropathic pain cannot be addressed by the present study. The answer to this important question relies primarily on the elucidation of their target mRNAs. However, miRNA may integratedly modulate several genes associated with both the nociceptive and analgesic systems, influencing the dramatic neuronal changes responsible for the development and maintenance of chronic pain conditions. Most important, miRNA expression in the nociceptive system shows not only spatiotemporal specificity but is also stimulus-dependent.
brain derived neurotrophic factor
complete Freund's adjuvant
dorsal root ganglion
immediate early gene
insulin-like growth factor 1
mitogen-activated protein kinase 3
nerve growth factor receptor Oprd1: opioid receptor, delta 1
phospholipase A2, group IVA (cytosolic, calcium-dependent)
real-time reverse transcription polymerase chain reaction
transient receptor potential cation channel, subfamily C, member 3
- 3' UTR:
three prime untranslated region
The authors are thankful to Profs. Margaret de Castro, and Angela Kaysel Cruz for providing equipment facilities. This project was supported by the São Paulo State Research Foundation-FAPESP (grant no. 07/00002-2), and the University of São Paulo research funds. R.K., F.C., and M.I.R. were supported by FAPESP fellowships.
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