Overexpression of miR-98 attenuates neuropathic pain development via targeting STAT3 in CCI rat models

MicroRNA (miRNA) are significant regulators of neuropathic pain development and neuroinflammation can contribute a lot to the progression of neuropathic pain. Recently, miR-98 has been reported to be involved in various diseases. However, little is known about the role of miR-98 in neuropathic pain development and neuroinflammation. Therefore, our study was aimed to investigate the function of miR-98 in neuropathic pain via establishing a rat model using chronic constriction injury (CCI) of the sciatic nerve. Here, we observed that miR-98 was downregulated in CCI rat models. Overexpression of miR-9 was able to inhibit neuropathic pain progression. Recently, STAT3 has been reported to serve a key role in various processes, including inflammation. Interestingly, our study indicated that STAT3 was dramatically upregulated and activated in CCI rats. By using informatics analysis, STAT3 was predicted as a direct target of miR-98 and the direct correlation was confirmed. Then, miR-98 was overexpressed in CCI rats and it was found that miR-98 was able to repress neuropathic pain development via inhibiting the neuroinflammation. As displayed, interleukin 6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) expression was obviously induced in CCI rats, while miR-98 reduced their protein levels. Finally, we found that overexpression of STAT3 reversed the inhibitory effect of miR-98 on neuropathic pain development. Taken these together, we reported that overexpression of miR-98 attenuated neuropathic pain development via targeting STAT3 in CCI rat models.     

miR-124-3p attenuates neuropathic pain induced by chronic sciatic nerve injury in rats via targeting EZH2

Emerging evidence has suggested that microRNAs play a critical role in neuropathic pain development. However, the biological role of miRNAs in regulating neuropathic pain remains barely known. In our present study, we found that miR-124-3p was significantly downregulated in rats after chronic sciatic nerve injury (CCI). In addition, it was showed that overexpression of miR-124-3p obviously repressed mechanical allodynia and heat hyperalgesia. Meanwhile, it has been reported that neuroinflammation can contribute a lot to neuropathic pain progression. Here, we found that inflammatory cytokine (IL-6, IL-1β, and TNF-⍺) protein expression in rats after CCI greatly increased and miR-124-3p mimics depressed inflammation cytokine levels. Consistently, miR-124-3p alleviated inflammation production in lipopolysaccharide-incubated spinal microglial cells. Bioinformatics analysis revealed that EZH2 acted as a direct target of miR-124-3p, which participated in the miR-124-3p-modulated effects on neuropathic pain development and neuroinflammation. We observed that miR-124-3p was able to promote neuroinflammation and neuropathic pain through targeting EZH2. The direct correlation between them was validated in our current study using dual-luciferase reporter assays. Subsequently, it was manifested that EZH2 abrogated the inhibitory role of miR-124-3p on neuropathic pain progression in CCI rats. Taken these together, our findings highlighted a novel contribution of miR-124-3p to neuropathic pain and indicated the possibilities for developing novel therapeutic options for neuropathic pain.     

MiR-134-5p attenuates neuropathic pain progression through targeting Twist1

Neuropathic pain is a kind of chronic pain because of dysfunctions of somatosensory nerve system. Recently, many studies have demonstrated that microRNAs (miRs) play crucial roles in neuropathic pain development. This study was designed to investigate the effects of miR-134-5p on the process of neuropathic pain progression in a rat model established by chronic sciatic nerve injury (CCI). First, we observed that miR-134-5p was significantly decreased in CCI rat models. Overexpression of miR-134-5p strongly alleviated neuropathic pain behaviors including mechanical and thermal hyperalgesia. Meanwhile, inflammatory cytokine expression, such as IL-6, IL-1β and TNF-α in CCI rats were greatly repressed by upregulation of miR-134-5p. Twist1 has been widely regarded as a poor prognosis biomarker in diverse diseases. Here, by using bioinformatic analysis, 3′-untranslated region (UTR) of Twist1 was predicted to be a downstream target of miR-134-5p in our study. Here, we found that overexpression of miR-134-5p was able to suppress Twist1 dramatically. Furthermore, it was exhibited that Twist1 was increased in CCI rats time-dependently and Twist1 was inhibited in vivo. Subsequently, downregulation of Twist1 in CCI rats could depress neuropathic pain progression via inhibiting neuroinflammation. In conclusion, our current study indicated that miR-134-5p may inhibit neuropathic pain development through targeting Twist1. Our findings suggested that miR-134-5p might provide a novel therapeutic target for neuropathic pain.     

DGCR5 attenuates neuropathic pain through sponging miR-330-3p and regulating PDCD4 in CCI rat models

Neuropathic pain caused by somatosensory nervous system dysfunction is a serious public health problem. Some long noncoding RNAs (lncRNAs) can participate in physiological processes involved in neuropathic pain. However, the effects of lncRNA DGCR5 in neuropathic pain have not been explored. Therefore, in our current study, we concentrated on the biological roles of DGCR5 in neuropathic pain. Here, it was observed that DGCR5 was significantly decreased in chronic sciatic nerve injury (CCI) rat models. DGCR5 overexpression was able to alleviate neuropathic pain development including mechanical and thermal hyperalgesia. In addition, the current understanding of miR-330-3p function in neuropathic pain remains largely incomplete. Here, we found that miR-330-3p was greatly increased in CCI rats and DGCR5 can modulate miR-330-3p expression negatively. Upregulation of DGCR5 repressed inflammation-correlated biomarkers including interleukin 6 (IL-6), tumor necrosis factor α, and IL-1β in CCI rats by sponging miR-330-3p. The negative correlation between DGCR5 and miR-330-3p was confirmed in our current study. Inhibition of miR-330-3p suppressed neuropathic pain progression by restraining neuroinflammation in vivo. In addition, PDCD4 was predicted as a downstream target of miR-330-3p. Furthermore, PDCD4 was significantly increased in CCI rats and DGCR5 regulated PDCD4 expression through sponging miR-330-3p in CCI rat models. Taken these together, it was implied that DGCR5/miR-330-3p/PDCD4 axis participated in neuropathic pain treatment.     

CRNDE enhances neuropathic pain via modulating miR-136/IL6R axis in CCI rat models

Neuropathic pain has been reported as a type of chronic pain due to the primary dysfunction of the somatosensory nervous system. It is the most serious types of chronic pain, which can lead to a significant public health burden. But, the understanding of the cellular and molecular pathogenesis of neuropathic pain is barely complete. Long noncoding RNAs (lncRNAs) have recently been regarded as modulators of neuronal functions. Growing studies have indicated lncRNAs can exert crucial roles in the development of neuropathic pain. Therefore, our present study focused on the potential role of the lncRNA Colorectal Neoplasia Differentially Expressed (CRNDE) in neuropathic pain progression. Firstly, a chronic constrictive injury (CCI) rat model was built. CRNDE was obviously increased in CCI rats. Interestingly, overexpression of CRNDE enhanced neuropathic pain behaviors. Neuroinflammation was induced by CRNDE and as demonstrated, interleukin-10 (IL-10), IL-1, IL-6, and tumor necrosis factor-α (TNF-α) protein levels in CCI rats were activated by LV-CRNDE. For another, miR-136 was obviously reduced in CCI rats. Previously, it is indicated that miR-136 participates in the spinal cord injury via an inflammation in a rat model. Here, firstly, we verified miR-136 could serve as CRNDE target. Loss of miR-136 triggered neuropathic pain remarkably via the neuroinflammation activation. Additionally, IL6R was indicated as a target of miR-136 and miR-136 regulated its expression. Subsequently, we confirmed that CRNDE could induce interleukin 6 receptor (IL6R) expression positively. Overall, it was implied that CRNDE promoted neuropathic pain progression via modulating miR-136/IL6R axis in CCI rat models.     

Upregulation of miR-183 represses neuropathic pain through inhibiton of MAP3K4 in CCI rat models

Many studies have verified that microRNAs contribute a lot to neuropathic pain progression. Furthermore, nerve-related inflammatory cytokines play vital roles in neuropathic pain progression. miR-183 has been identified to have a common relationship with multiple pathological diseases. However, the potential effects of miR-183 in the process of neuropathic pain remain undetermined. Therefore, we performed the current study with the purpose of finding the functions of miR-183 in neuropathic pain progression using a chronic sciatic nerve injury (CCI) rat model. We demonstrated that miR-183 expression levels were evidently reduced in CCI rats in contrast with the control group. Overexpression of miR-183 produced significant relief of mechanical hyperalgesia, as well as thermal hyperalgesia in CCI rats. Furthermore, neuropathic pain-correlated inflammatory cytokine expression levels containing interleukin-6 (IL-6) and interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2) were obviously inhibited by upregulation of miR-183. Meanwhile, dual-luciferase reporter assays showed MAP3K4 was a direct downstream gene of miR-183. The expression levels of MAP3K4 were modulated by the increased miR-183 negatively, which lead to the downregulation of IL-6, IL-1β, and COX-2, and then reduced neuropathic pain progression, respectively. Overall, our study pointed out that miR-183 was a part of the negative regulator which could relieve neuropathic pain by targeting MAP3K4. Thus it may provide a new clinical treatment for neuropathic pain patients clinical therapy.     

miR-32-5p-mediated Dusp5 downregulation contributes to neuropathic pain

Previous studies have demonstrated that microRNAs (miRNAs) play important roles in the pathogenesis of neuropathic pain. In the present study, we found that miR-32-5p was significantly upregulated in rats after spinal nerve ligation (SNL), specifically in the spinal microglia of rats with SNL. Functional assays showed that knockdown of miR-32-5p greatly suppressed mechanical allodynia and heat hyperalgesia, and decreased inflammatory cytokine (IL-1β, TNF-α and IL-6) protein expression in rats after SNL. Similarly, miR-32-5p knockdown alleviated cytokine production in lipopolysaccharide (LPS)-treated spinal microglial cells, whereas its overexpression had the opposite effect. Mechanistic investigations revealed Dual-specificity phosphatase 5 (Dusp5) as a direct target of miR-32-5p, which is involved in the miR-32-5p-mediated effects on neuropathic pain and neuroinflammation. We demonstrated for the first time that miR-32-5p promotes neuroinflammation and neuropathic pain development through regulation of Dusp5. Our findings highlight a novel contribution of miR-32-5p to the process of neuropathic pain, and suggest possibilities for the development of novel therapeutic options for neuropathic pain.     

LINC00657 expedites neuropathic pain development by modulating miR-136/ZEB1 axis in a rat model

Long non-coding RNAs (lncRNAs) are involved in the progression of several diseases. The interactions among lncRNAs, microRNA (miRNAs) or their targeting genes are reported to play crucial roles in the development of diseases. LINC00657 is observed to be upregulated in several cancers. However, the biological role of LINC00657 in neuropathic pain progress is unclear. Hence, in our study, we aimed to investigate the function of LINC00657 in neuropathic pain development. A chronic constriction injury (CCI) rat model was established, and we found that LINC00657 was greatly increased in CCI rats associated with a decrease of miR-136. Inhibition of LINC00657 suppressed neuropathic pain via alleviating mechanical and thermal hyperalgesia. In addition, miR-136 overexpression can also inhibit the neuropathic pain development. MiR-136 was predicted to serve as a miRNA target of LINC00657, and dual-luciferase reporter assay confirmed the correlation between LINC00657 and miR-136. Moreover, we observed that the decrease of LINC00657 was able to inhibit the neuroinflammation of CCI rats by targeting expression of cyclooxygenase-2, tumor necrosis factor-α and interleukin-1β while miR-136 inhibitors reversed this phenomenon. Next, by using bioinformatics analysis, ZEB1 was predicted as a direct target of miR-136, and miR-136 could negatively modulate ZEB1 expression. Besides these, ZEB1 was remarkably increased in the CCI rats. Knockdown of ZEB1 can inhibit neuropathic pain development, while miR-136 inhibitors can reverse it. In conclusion, it was implied that LINC00657 can induce the neuropathic pain development via regulating miR-136/ZEB1 axis.     

miR-98 acts as an inhibitor in chronic constriction injury-induced neuropathic pain via downregulation of high-mobility group AT-hook 2

Neuropathic pain, resulting from somatosensory nervous system dysfunction, remains a serious public health problem worldwide. microRNAs are involved in the physiological processes of neuropathic pain. However, the biological roles of miR-98 in neuropathic pain development have not been investigated. Therefore, in our current study, we focused on the effects of miR-98 in neuropathic pain. It was shown that miR-98 was significantly downregulated in chronic sciatic nerve injury (CCI) rat models. In addition, high mobility group A2 (HMGA2) was obviously upregulated in CCI rats. Overexpression of miR-98 inhibited neuropathic pain progression, including mechanical and thermal hyperalgesia. By a bioinformatics analysis, HMGA2 was predicted as a direct target of miR-98. The negative correlation between miR-98 and HMGA2 was validated in our present study. Furthermore, overexpression of miR-98 dramatically repressed HMGA2 protein and messenger RNA (mRNA) expression. Neuroinflammation participates in neural-immune interactions, which can contribute to the neuropathic pain development. Meanwhile, we found that inflammatory cytokine (interleukin [IL]-6, IL-1β, and COX-2) protein expression in rats infected with LV-miR-98 was greatly suppressed. Taking these results together, we concluded that miR-98 might depress neuropathic pain development through modulating HMGA2.     

Retracted: MicroRNA-217 relieved neuropathic pain through targeting toll-like receptor 5 expression

Neuropathic pain is the most common chronic pain that is caused by nerve injury or disease that influences the nervous system. Increasing evidence suggested that microRNAs (miRNAs) play a crucial role in neuropathic pain and neuroinflammation development. However, the functional role of miR-217 in the development of neuropathic pain remains unknown. In this study, we used rats to establish a neuropathic pain model and showed that the miR-217 expression level was upregulated in the spinal dorsal horn of bilateral sciatic nerve chronic constriction injury (bCCI). However, the expression of miR-217 was not changed in the anterior cingulated cortex (ACC), hippocampus, and dorsal root ganglion (DRG) of bCCI rats. Ectopic expression of miR-217 attenuated neuropathic pain and suppressed neuroinflammation expression in vivo. We identified toll-like receptor 5 (TLR5) as a direct target gene of miR-217 in the PC12 cell. In addition, we demonstrated that the expression level of TLR5 was upregulated in bCCI rats. Moreover, restoration of TLR5 rescued the inhibitory roles induced by miR-217 overexpression on neuropathic pain and neuroinflammation development. These data suggested that miR-217 played a pivotal role in the development of neuropathic pain partly through regulating TLR5 expression.     

miR-21-5p inhibits neuropathic pain development via directly targeting C-C motif ligand 1 and tissue inhibitor of metalloproteinase-3

MicroRNAs (miRNA) play important roles in neuroinflammation and neuropathic pain development; however, the underlying mechanism requires further investigation. The expression of miR-21-5p was remarkably upregulated in chronic constrictive injury (CCI) rat model. A significant alleviated neuropathic pain development and reduced the expression of cytokines was observed in CCI rat after exogenous injection of miR-21-5p mimic. The dual-luciferase analysis revealed that tissue inhibitor of metalloproteinase-3 (TIMP3) and chemokines C-C motif ligand 1 (CCL1) was direct downstream target of miR-21-5p. Moreover, silencing of TIMP3 and CCL1 could rescue mechanical allodynia, thermal hyperalgesia and cytokine release in CCI rat, suggesting that TIMP3 and CCL1 exert their function by mediating neuroinflammation in neuropathic pain development. Therefore, we have identified a novel miR-21-5p–CCL1/TIMP3-cytokine axis in regulation of neuropathic pain development in CCI rat model, which is valuable for enhancing our understanding of neuropathic pain and developing miRNAs as potential therapeutic options in the future.     

Early systemic granulocyte-colony stimulating factor treatment attenuates neuropathic pain after peripheral nerve injury

Recent studies have shown that opioid treatment can reduce pro-inflammatory cytokine production and counteract various neuropathic pain syndromes. Granulocyte colony-stimulating factor (G-CSF) can promote immune cell differentiation by increasing leukocytes (mainly opioid-containing polymorphonuclear (PMN) cells), suggesting a potential beneficial role in treating chronic pain. This study shows the effectiveness of exogenous G-CSF treatment (200 μg/kg) for alleviating thermal hyperalgesia and mechanical allodynia in rats with chronic constriction injury (CCI), during post-operative days 1-25, compared to that of vehicle treatment. G-CSF also increases the recruitment of opioid-containing PMN cells into the injured nerve. After CCI, single administration of G-CSF on days 0, 1, and 2, but not on day 3, relieved thermal hyperalgesia, which indicated that its effect on neuropathic pain had a therapeutic window of 0-48 h after nerve injury. CCI led to an increase in the levels of interleukin-6 (IL-6) mRNA and tumor necrosis factor-α (TNF-α) protein in the dorsal root ganglia (DRG). These high levels of IL-6 mRNA and TNF-α were suppressed by a single administration of G-CSF 48-144 h and 72-144 h after CCI, respectively. Furthermore, G-CSF administered 72-144 h after CCI suppressed the CCI-induced upregulation of microglial activation in the ipsilateral spinal dorsal horn, which is essential for sensing neuropathic pain. Moreover, the opioid receptor antagonist naloxone methiodide (NLXM) reversed G-CSF-induced antinociception 3 days after CCI, suggesting that G-CSF alleviates hyperalgesia via opioid/opioid receptor interactions. These results suggest that an early single systemic injection of G-CSF alleviates neuropathic pain via activation of PMN cell-derived endogenous opioid secretion to activate opioid receptors in the injured nerve, downregulate IL-6 and TNF-α inflammatory cytokines, and attenuate microglial activation in the spinal dorsal horn. This indicates that G-CSF treatment can suppress early inflammation and prevent the subsequent development of neuropathic pain.     

MiR‐150 alleviates neuropathic pain via inhibiting toll‐like receptor 5

MicroRNAs (miRNAs) are reported as vital participators in the pathophysiological course of neuropathic pain. However, the underlying mechanisms of the functional roles of miRNAs in neuropathic pain are largely unknown. This study was designed to explore the potential role of miR‐150 in regulating the process of neuropathic pain in a rat model established by chronic sciatic nerve injury (CCI). Overexpression of miR‐150 greatly alleviated neuropathic pain development and reduced inflammatory cytokine expression, including COX‐2, interleukin IL‐6, and tumor necrosis factor (TNF)‐α in CCI rats. By bioinformatic analysis, 3′‐untranslated region (UTR) of Toll‐like receptor (TLR5) was predicted to be a target of miR‐150. TLR5 commonly serves as an important regulator of inflammation. Overexpression of miR‐150 significantly suppressed the expression of TLR5 in vitro and in vivo. Furthermore, upregulation of TLR5 decreased the miR‐150 expression and downregulation of TLR5 increased miR‐150, respectively. Overexpression of TLR5 significantly reversed the miR‐150‐induced suppressive effects on neuropathic pain. In conclusion, our current study indicates that miR‐150 may inhibit neuropathic pain development of CCI rats through inhibiting TLR5‐mediated neuroinflammation. Our findings suggest that miR‐150 may provide a novel therapeutic target for neuropathic pain treatment.     

Knockdown of Linc00052 alleviated spinal nerve ligation-triggered neuropathic pain through regulating miR-448 and JAK1

The dysfunction of the nervous system contributes to neuropathic pain. Long noncoding RNAs are reported to participate in neuropathic pain. Recently, Linc00052 is implicated to be closely associated with multiple diseases. Nevertheless, the mechanisms of Linc00052 remain barely explored in neuropathic pain development. Currently, spinal nerve ligation (SNL) triggered neuropathic pain was employed in our investigation. Here, we assessed the function of Linc00052 in SNL rat models. Interestingly, we reported Linc00052 was significantly elevated in SNL rats. Loss of Linc00052 could reduce neuropathic pain progression via regulating the behaviors of neuropathic pain. Additionally, knockdown of Linc00052 repressed the processes of neuroinflammation. Interleukin (IL)-6 and tumor necrosis factor α level were inhibited while IL-10 was induced by the silence of Linc00052. Moreover, we predicted miR-448 can serve as a target of Linc00052. miR-448 exerts a crucial power in several diseases. Currently, we exhibited miR-448 was remarkably downregulated in SNL rats. RNA immunoprecipitation experiments validated the association between miR-448 and Linc00052. Inhibition of Linc00052 could reverse the roles of miR-448 on neuropathic pain development. Furthermore, Janus kinase 1 (JAK1) was displayed as the putative target of miR-448 in the present investigation. It was showed that JAK1 was induced in SNL rats. Loss of miR-448 could dramatically induce the expression of JAK1, which was rescued by knockdown of Linc00052. Taken these together, our study implied that Linc00052 functioned as a novel target of neuropathic pain via sponging miR-448 and regulating JAK1.     

E3 Ubiquitin Ligase c-cbl Inhibits Microglia Activation After Chronic Constriction Injury

E3 ubiquitin ligase c-Caritas B cell lymphoma (c-cbl) is associated with negative regulation of receptor tyrosine kinases, signal transduction of antigens and cytokine receptors, and immune response. However, the expression and function of c-cbl in the regulation of neuropathic pain after chronic constriction injury (CCI) are unknown. In rat CCI model, c-cbl inhibited the activation of spinal cord microglia and the release of pro-inflammatory factors including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6), which alleviated mechanical and heat pain through down-regulating extracellular signal-regulated kinase (ERK) pathway. Additionally, exogenous TNF-α inhibited c-cbl protein level vice versa. In the primary microglia transfected with c-cbl siRNA, when treated with TNF-α or TNF-α inhibitor, the corresponding secretion of IL-1β and IL-6 did not change. In summary, CCI down-regulated c-cbl expression and induced the activation of microglia, then activated microglia released inflammatory factors via ERK signaling to cause pain. Our data might supply a novel molecular target for the therapy of CCI-induced neuropathic pain.     

Loganin prevents chronic constriction injury-provoked neuropathic pain by reducing TNF-α/IL-1β-mediated NF-κB activation and Schwann cell demyelination

BackgroundPeripheral nerve injury can produce chronic and ultimately neuropathic pain. The chronic constriction injury (CCI) model has provided a deeper understanding of nociception and chronic pain. Loganin is a well-known herbal medicine with glucose-lowering action and neuroprotective activity.PurposeThis study investigated the molecular mechanisms by which loganin reduced CCI-induced neuropathic pain.MethodsSprague–Dawley rats were randomly divided into four groups: sham, sham+loganin, CCI and CCI+loganin. Loganin (1 or 5 mg/kg/day) was injected intraperitoneally once daily for 14 days, starting the day after CCI. For behavioral testing, mechanical and thermal responses were assessed before surgery and on d1, d3, d7 and d14 after surgery. Sciatic nerves (SNs) were collected to measure proinflammatory cytokines. Proximal and distal SNs were collected separately for Western blotting and immunofluorescence studies.ResultsThermal hyperalgesia and mechanical allodynia were reduced in the loganin-treated group as compared to the CCI group. Loganin (5 mg/kg/day) prevented CCI from inducing proinflammatory cytokines (TNF-α, IL-1β), inflammatory proteins (TNF-α, IL-1β, pNFκB, pIκB/IκB, iNOS) and receptor (TNFR1, IL-1R), adaptor protein (TRAF2) of TNF-α, and Schwann cell demyelination and axonal damage. Loganin also blocked IκB phosphorylation (p-IκB). Double immunofluorescent staining further demonstrated that pNFκB/pIκB protein was reduced by loganin in Schwann cells on d7 after CCI. In the distal stumps of injured SN, Schwann cell demyelination was correlated with pain behaviors in CCI rats.ConclusionOur findings indicate that loganin improves CCI-induced neuroinflammation and pain behavior by downregulating TNF-α/IL-1β-dependent NF-κB activation.     

Morin Mitigates Chronic Constriction Injury (CCI)-Induced Peripheral Neuropathy by Inhibiting Oxidative Stress Induced PARP Over-Activation and Neuroinflammation

Neuropathic pain is initiated or caused due to the primary lesion or dysfunction in the nervous system and is proposed to be linked to a cascade of events including excitotoxicity, oxidative stress, neuroinflammation and apoptosis. Oxidative/nitrosative stress aggravates the neuroinflammation and neurodegeneration through poly (ADP) ribose polymerase (PARP) overactivation. Hence, the present study investigated the antioxidant and anti-inflammatory effects of the phytoconstituent; morin in chronic constriction injury (CCI) induced neuropathy. Neuropathic pain was induced by chronic constriction of the left sciatic nerve in rats, and the effect of morin (15 and 30 mg/kg, p.o.) was evaluated by measuring behavioural and biochemical changes. Mechanical, chemical and thermal stimuli confirmed the CCI-induced neuropathic pain and treatment with morin significantly improved these behavioural deficits and improved the sciatic functional index by the 14th day after CCI induction. After 14 days of CCI induction, oxidative/nitrosative stress and inflammatory markers were elevated in rat lumbar spinal cord. Oxidative stress induced PARP overactivation resulted in depleted levels of ATP and elevated levels of poly (ADP) ribose (PAR). Treatment with morin reduced the levels of nitrites, restored glutathione levels and abrogated the oxidant induced DNA damage. It also mitigated the increased levels of TNF-α and IL-6. Protein expression studies confirmed the PARP inhibition and anti-inflammatory activity of morin. Findings of this study suggest that morin, by virtue of its antioxidant properties, limited PARP overactivation and neuroinflammation and protected against CCI induced functional, behavioural and biochemical deficits.     

MiR-183-5p Alleviates Chronic Constriction Injury-Induced Neuropathic Pain Through Inhibition of TREK-1

MicroRNAs have been implicated in nerve injury and neuropathic pain. In the previous study we had shown that miR-96 can attenuate neuropathic pain through inhibition of Nav1.3. In this study, we investigated the role of miR-183, a same cluster member of microRNA with miR-96, in neuropathic pain and its potential mechanisms. We found that the expression level of miR-183-5p in dorsal root ganglion was decreased with the development of neuropathic pain induced by chronic constriction sciatic nerve injury (CCI). By contrast, the TREK-1, a K⁺ channel, was increased. Further investigation identified that intrathecal injection of miR-183-5p mimic efficiently ameliorated neuropathic pain and inhibited the expression of TREK-1, a predicted target gene of miR-183-5p. Luciferase assays confirmed the binding of miR-183-5p and TREK-1. In addition, over-expression of TREK-1 blocked the roles of miR-183-5p in neuropathic pain. Our findings suggested that miR-183-5P participated in the regulation of CCI-induced neuropathic pain through inhibiting the expression of TREK-1.