Fumagillin Attenuates Spinal Angiogenesis, Neuroinflammation, and Pain in Neuropathic Rats after Chronic Constriction Injury

Introduction: Angiogenesis in the central nervous system is visible in animal models of neuroinflammation and bone cancer pain. However, whether spinal angiogenesis exists and contributes to central sensitization in neuropathic pain remains unclear. This study analyzes the impact of angiogenesis on spinal neuroinflammation in neuropathic pain. Methods: Rats with chronic constriction injury (CCI) to the sciatic nerve underwent the implantation of an intrathecal catheter. Fumagillin or vascular endothelial growth factor-A antibody (anti-VEGF-A) was administered intrathecally. Nociceptive behaviors, cytokine immunoassay, Western blot, and immunohistochemical analysis assessed the effect of angiogenesis inhibition on CCI-induced neuropathic pain. Results: VEGF, cluster of differentiation 31 (CD31), and von Willebrand factor (vWF) expressions increased after CCI in the ipsilateral lumbar spinal cord compared to that in the contralateral side of CCI and control rats from post-operative day (POD) 7 to 28, with a peak at POD 14. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 concentrations, but not IL-10 levels, also increased in the ipsilateral spinal cord after CCI. Fumagillin and anti-VEGF-A reduced CCI-induced thermal hyperalgesia from POD 5 to 14 and mechanical allodynia from POD 3 to 14. Fumagillin reduced CCI-upregulated expressions of angiogenic factors and astrocytes. Furthermore, fumagillin decreased TNF-α and IL-6 amounts and increased IL-10 levels at POD 7 and 14, but not IL-1β concentrations. Conclusions: Fumagillin significantly ameliorates CCI-induced nociceptive sensitization, spinal angiogenesis, and astrocyte activation. Our results suggest that angiogenesis inhibitor treatment suppresses peripheral neuropathy-induced central angiogenesis, neuroinflammation, astrocyte activation, and neuropathic pain.

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Fumagillin Attenuates Spinal Angiogenesis, Neuroinflammation, and Pain in Neuropathic Rats After Chronic Constriction Injury

10.21203/rs.3.rs-741520/v1 ◽

2021 ◽

Author(s):

Zhi-Hong Wen ◽

Shi-Ying Huang ◽

Hsiao-Mei Kuo ◽

Chao-Ting Chen ◽

Nan-Fu Chen ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Chronic Constriction Injury ◽

Angiogenesis Inhibitor ◽

Thermal Hyperalgesia ◽

Lumbar Spinal Cord ◽

Astrocyte Activation ◽

Anti Vegf ◽

Tnf Α ◽

The Impact

Abstract Background Angiogenesis in the central nervous system is visible in animal models of neuroinflammation and bone cancer pain. However, whether spinal angiogenesis exists and contributes to central sensitization in neuropathic pain remains unclear. This study analyzed the impact of angiogenesis on spinal neuroinflammation in neuropathic pain. Methods Rats with chronic constriction injury (CCI) to sciatic nerve underwent implantation of an intrathecal catheter. Fumagillin or vascular endothelial growth factor-A antibody (anti-VEGF-A) was administered intrathecally. Nociceptive behaviors, cytokine immunoassay, Western blot, and immunohistochemical analysis assessed the effect of angiogenesis inhibition on CCI-induced neuropathic pain. Results VEGF, cluster of differentiation 31 (CD31), and von Willebrand factor (vWF) expressions increased after CCI in the ipsilateral lumbar spinal cord compared to that in the contralateral side of CCI and control rats from postoperative day (POD) 7 to 28, with a peak at POD 14. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 concentrations, but not IL-10 levels, also increased in the ipsilateral spinal cord after CCI. Fumagillin and anti-VEGF-A reduced CCI-induced thermal hyperalgesia from POD 5 to 14 and mechanical allodynia from POD 3 to 14. Fumagillin reduced CCI-upregulated expressions of angiogenic factors and astrocytes. Furthermore, fumagillin decreased TNF-α and IL-6 amounts and increased IL-10 levels at POD 7 and 14, but not IL-1β concentrations. Conclusions Fumagillin significantly ameliorates CCI-induced nociceptive sensitization, spinal angiogenesis and astrocyte activation. Our results suggest that angiogenesis inhibitor treatment suppresses peripheral neuropathy-induced central angiogenesis, neuroinflammation, astrocyte activation, and neuropathic pain.

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Short-chain fatty acids contribute to neuropathic pain via regulating microglia activation and polarization

Molecular Pain ◽

10.1177/1744806921996520 ◽

2021 ◽

Vol 17 ◽

pp. 174480692199652

Author(s):

Feng Zhou ◽

Xian Wang ◽

Baoyu Han ◽

Xiaohui Tang ◽

Ru Liu ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Thermal Hyperalgesia ◽

Short Chain Fatty Acids ◽

Antibiotic Administration ◽

Tnf Α ◽

Microglia Polarization ◽

Inflammatory Phenotype ◽

Phenotype Markers ◽

Anti Inflammatory

Microglia activation and subsequent pro-inflammatory responses play a key role in the development of neuropathic pain. The process of microglia polarization towards pro-inflammatory phenotype often occurs during neuroinflammation. Recent studies have demonstrated an active role for the gut microbiota in promoting microglial full maturation and inflammatory capabilities via the production of Short-Chain Fatty Acids (SCFAs). However, it remains unclear whether SCFAs is involved in pro-inflammatory/anti-inflammatory phenotypes microglia polarization in the neuropathic pain. In the present study, chronic constriction injury (CCI) was used to induce neuropathic pain in mice, the mechanical withdrawal threshold, thermal hyperalgesia were accomplished. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), pro-inflammatory phenotype markers including CD68, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and anti-inflammatory phenotype markers including CD206, IL-4 in the hippocampus and spinal cord were determined on day 21 after CCI. The results showed that CCI produced mechanical allodynia and thermal hyperalgesia, and also increased the expressions of microglia markers (Iba1, CD11b) and pro-inflammatory phenotype markers (CD68, IL-1β, and TNF-α), but not anti-inflammatory phenotype marker (CD206, IL-4) in the hippocampus and spinal cord, accompanied by increased SCFAs in the gut. Notably, antibiotic administration reversed these abnormalities, and its effects was also bloked by SCFAs administration. In conclusion, data from our study suggest that CCI can lead to mechanical and thermal hyperalgesia, while SCFAs play a key role in the pathogenesis of neuropathic pain by regulating microglial activation and subsequent pro-inflammatory phenotype polarization. Antibiotic administration may be a new treatment for neuropathic pain by reducing the production of SCFAs and further inhibiting the process of microglia polarization.

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Dynamic effects of TNF-α on synaptic transmission in mice over time following sciatic nerve chronic constriction injury

Journal of Neurophysiology ◽

10.1152/jn.01088.2012 ◽

2013 ◽

Vol 110 (7) ◽

pp. 1663-1671 ◽

Cited By ~ 23

Author(s):

Hongmei Zhang ◽

Haijun Zhang ◽

Patrick M. Dougherty

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Synaptic Transmission ◽

Dorsal Horn ◽

Nerve Injury ◽

Chronic Constriction Injury ◽

Synaptic Signaling ◽

Tnf Α ◽

Over Time

Nerve injury-induced central sensitization can manifest as an increase in excitatory synaptic transmission and/or as a decrease in inhibitory synaptic transmission in spinal dorsal horn neurons. Cytokines such as tumor necrosis factor-α (TNF-α) are induced in the spinal cord under various injury conditions and contribute to neuropathic pain. In this study we examined the effect of TNF-α in modulating excitatory and inhibitory synaptic input to spinal substantia gelatinosa (SG) neurons over time in mice following chronic constriction injury (CCI) of the sciatic nerve. Whole cell patch-clamp studies from SG neurons showed that TNF-α enhanced overall excitability of the spinal cord early in time following nerve injury 3 days after CCI compared with that in sham control mice. In contrast, the effects of TNF were blunted 14 days after CCI in nerve-injured mice compared with sham surgery mice. Immunohistochemical staining showed that the expression of TNF-α receptor 1 (TNFR1) was increased at 3 days but decreased at 14 days following CCI in the ipsilateral vs. the contralateral spinal cord dorsal horn. These results suggest that TNF-α acting at TNFR1 is important in the development of neuropathic pain by facilitating excitatory synaptic signaling in the acute phases after nerve injury but has a reduced effect on spinal neuron signaling in the later phases of nerve injury-induced pain. Failure of the facilatory effects of TNF-α on excitatory synaptic signaling in the dorsal horn to resolve following nerve injury may be an important component in the transition between acute and chronic pain conditions.

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Nrf2 Activation Attenuates Chronic Constriction Injury-induced Neuropathic Pain via Induction of PGC-1α-mediated Mitochondrial Biogenesis in the Spinal Cord

10.21203/rs.3.rs-723909/v1 ◽

2021 ◽

Author(s):

Jia Sun ◽

Jia-Yan Li ◽

Long-Qing Zhang ◽

Dan-Yang Li ◽

Jia-Yi Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Neuropathic Pain ◽

Mitochondrial Dysfunction ◽

Mitochondrial Biogenesis ◽

Chronic Constriction Injury ◽

Clinical Investigation ◽

Thermal Hyperalgesia ◽

Related Factor ◽

Dependent Manner

Abstract BackgroundNeuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of antioxidant response system. In this study, we investigated whether RTA-408 (a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms.MethodsNeuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von-Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB.ResultsRTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2 dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that PGC-1α activator also exhibited a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the pre-injection of PGC-1α inhibitor.ConclusionsNrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.

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Reciprocal Regulatory Interaction between TRPV1 and Kinin B1 Receptor in a Rat Neuropathic Pain Model

International Journal of Molecular Sciences ◽

10.3390/ijms21030821 ◽

2020 ◽

Vol 21 (3) ◽

pp. 821 ◽

Cited By ~ 1

Author(s):

Veronica Cernit ◽

Jacques Sénécal ◽

Rahmeh Othman ◽

Réjean Couture

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Mrna Expression ◽

Thermal Hyperalgesia ◽

Mrna Levels ◽

Regulatory Interaction ◽

B1 Receptor ◽

Tnf Α ◽

Kinin B1 Receptor ◽

Sensory Fibers

Kinins are mediators of pain and inflammation and evidence suggests that the inducible kinin B1 receptor (B1R) is involved in neuropathic pain (NP). This study investigates whether B1R and TRPV1 are colocalized on nociceptors and/or astrocytes to enable regulatory interaction either directly or through the cytokine pathway (IL-1β, TNF-α) in NP. Sprague Dawley rats were subjected to unilateral partial sciatic nerve ligation (PSNL) and treated from 14 to 21 days post-PSNL with antagonists of B1R (SSR240612, 10 mg·kg−1, i.p.) or TRPV1 (SB366791, 1 mg·kg−1, i.p.). The impact of these treatments was assessed on nociceptive behavior and mRNA expression of B1R, TRPV1, TNF-α, and IL-1β. Localization on primary sensory fibers, astrocytes, and microglia was determined by immunofluorescence in the lumbar spinal cord and dorsal root ganglion (DRG). Both antagonists suppressed PSNL-induced thermal hyperalgesia, but only SB366791 blunted mechanical and cold allodynia. SSR240612 reversed PSNL-induced enhanced protein and mRNA expression of B1R and TRPV1 mRNA levels in spinal cord while SB366791 further increased B1R mRNA/protein expression. B1R and TRPV1 were found in non-peptide sensory fibers and astrocytes, and colocalized in the spinal dorsal horn and DRG, notably with IL-1β on astrocytes. IL-1β mRNA further increased under B1R or TRPV1 antagonism. Data suggest that B1R and TRPV1 contribute to thermal hyperalgesia and play a distinctive role in allodynia associated with NP. Close interaction and reciprocal regulatory mechanism are suggested between B1R and TRPV1 on astrocytes and nociceptors in NP.

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Long-term Application of Glycine Transporter Inhibitors Acts Antineuropathic and Modulates Spinal N-methyl-d-aspartate Receptor Subunit NR-1 Expression in Rats

Anesthesiology ◽

10.1097/aln.0000000000000203 ◽

2014 ◽

Vol 121 (1) ◽

pp. 160-169 ◽

Cited By ~ 15

Author(s):

Franziska Barthel ◽

Andrea Urban ◽

Lukas Schlösser ◽

Volker Eulenburg ◽

Robert Werdehausen ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Side Effects ◽

Mechanical Allodynia ◽

Chronic Constriction Injury ◽

Thermal Hyperalgesia ◽

Receptor Expression ◽

Dependent Manner ◽

Receptor Subunit ◽

Aspartate Receptor

Abstract Background: Dysfunction of spinal glycinergic neurotransmission is a major pathogenetic factor in neuropathic pain. The synaptic glycine concentration is controlled by the two glycine transporters (GlyT) 1 and 2. GlyT inhibitors act antinociceptive in various animal pain models when applied as bolus. Yet, in some studies, severe neuromotor side effects were reported. The aim of the current study was to elucidate whether continuous inhibition of GlyT ameliorates neuropathic pain without side effects and whether protein expression of GlyT1, GlyT2, or N-methyl-d-aspartate receptor subunit NR-1 in the spinal cord is affected. Methods: In the chronic constriction injury model of neuropathic pain, male Wistar rats received specific GlyT1 and GlyT2 inhibitors (ALX5407 and ALX1393; Sigma-Aldrich®, St. Louis, MO) or vehicle for 14 days via subcutaneous osmotic infusion pumps (n = 6). Mechanical allodynia and thermal hyperalgesia were assessed before, after chronic constriction injury, and every 2 days during substance application. At the end of behavioral assessment, the expression of GlyT1, GlyT2, and NR-1 in the spinal cord was determined by Western blot analysis. Results: Both ALX5407 and ALX1393 ameliorated thermal hyperalgesia and mechanical allodynia in a time- and dose-dependent manner. Respiratory or neuromotor side effects were not observed. NR-1 expression in the ipsilateral spinal cord was significantly reduced by ALX5407, but not by ALX1393. The expression of GlyT1 and GlyT2 remained unchanged. Conclusions: Continuous systemic inhibition of GlyT significantly ameliorates neuropathic pain in rats. Thus, GlyT represent promising targets in pain research. Modulation of N-methyl-d-aspartate receptor expression might represent a novel mechanism for the antinociceptive action of GyT1 inhibitors.

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Gastrodia elata Blume Polysaccharides Attenuate Vincristine-Evoked Neuropathic Pain through the Inhibition of Neuroinflammation

Mediators of Inflammation ◽

10.1155/2021/9965081 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Hengtao Xie ◽

Yingying Chen ◽

Wei Wu ◽

Xiaobo Feng ◽

Kairong Du

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Inflammatory Cytokines ◽

Thermal Hyperalgesia ◽

Mrna Levels ◽

Gastrodia Elata ◽

Neuroprotective Effects ◽

Gastrodia Elata Blume ◽

Tnf Α

Vincristine (Vin) is a well-known antitumor agent that frequently evokes neuropathic pain and decreases the quality of life of patients. Polysaccharides (GBP) extracted from Gastrodia elata Blume have been demonstrated to possess anti-inflammatory and neuroprotective effects in vivo; however, the effects of GBP on Vin-induced neuropathic pain remain unknown. The present study is aimed at exploring the alleviative potential of GBP against chemotherapy-evoked peripheral neuropathy to better understand and extend its pharmacological application. Vin was administered intraperitoneally to evoke neuropathic pain. GBP was orally administered for 21 days. The mechanical allodynia and thermal hyperalgesia were assessed using the Von Frey test and hot-plate test. Histopathological changes were assessed by hematoxylin and eosin staining. ELISA kits were used to measure the levels of inflammatory cytokines in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). qRT-PCR was employed to examine the expression of inflammatory cytokines and Sirtuin1 (SIRT1) in the sciatic nerve, spinal cord, and DRG. Our findings revealed that GBP treatment enhanced the paw withdrawal latency and paw withdrawal threshold and restored Vin-induced sciatic nerve damage in rats. GBP also attenuated the Vin-induced increase of proinflammatory cytokine levels, including IL-6, IL-8, TNF-α, IL-1β, and NF-κB. On the molecular level, treatment with GBP downregulated the mRNA levels of IL-6, IL-8, TNF-α, and IL-1β in the sciatic nerve, spinal cord, and DRG. Meanwhile, GBP increased SIRT1 activity and mRNA expression levels. Our data indicated that GBP exerted a potential protective effect against chemotherapy-induced neuropathic pain which might be mediated via the inhibition of neuroinflammation.

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Nrf2 Activation Attenuates Chronic Constriction Injury-Induced Neuropathic Pain via Induction of PGC-1α-Mediated Mitochondrial Biogenesis in the Spinal Cord

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9577874 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Jia Sun ◽

Jia-Yan Li ◽

Long-Qing Zhang ◽

Dan-Yang Li ◽

Jia-Yi Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Neuropathic Pain ◽

Mitochondrial Dysfunction ◽

Mitochondrial Biogenesis ◽

Chronic Constriction Injury ◽

Thermal Hyperalgesia ◽

Related Factor ◽

Dependent Manner ◽

Nrf2 Activation

Background. Neuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of the antioxidant response system. In this study, we investigated whether RTA-408 (RTA, a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms. Methods. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB. Results. RTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2-dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that the PGC-1α activator also induced a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the preinjection of the PGC-1α inhibitor. Conclusions. Nrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.

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Herbal Prescription SH003 Alleviates Docetaxel-Induced Neuropathic Pain in C57BL/6 Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/4120334 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Kangwook Lee ◽

Jin Mo Ku ◽

Yu-Jeong Choi ◽

Hyun Ha Hwang ◽

Miso Jeong ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Peripheral Neuropathy ◽

Mechanical Allodynia ◽

Nerve Fibers ◽

Lumbar Spinal Cord ◽

Breast Cancers ◽

Tnf Α ◽

Sciatic Nerves ◽

Herbal Prescription

Docetaxel-based therapy has been applied to kill cancers including lung and breast cancers but frequently causes peripheral neuropathy such as mechanical allodynia. Lack of effective drugs for chemotherapy-induced peripheral neuropathy (CIPN) treatment leads us to find novel drugs. Here, we investigated whether and how novel anticancer herbal prescription SH003 alleviates mechanical allodynia in mouse model of docetaxel-induced neuropathic pain. Docetaxel-induced mechanical allodynia was evaluated using von Frey filaments. Nerve damage and degeneration in paw skin of mice were investigated by immunofluorescence staining. Neuroinflammation markers in bloodstream, lumbar (L4-L6) spinal cord, and sciatic nerves were examined by ELISA or western blot analysis. Docetaxel (15.277 mg/kg) was intravenously injected into the tail vein of C57BL/6 mice, and mechanical allodynia was followed up. SH003 (557.569 mg/kg) was orally administered at least 60 min before the mechanical allodynia test, and von Frey test was performed twice. Docetaxel injection induced mechanical allodynia, and SH003 administration restored withdrawal threshold. Meanwhile, degeneration of intraepidermal nerve fibers (IENF) was observed in docetaxel-treated mice, but SH003 treatment suppressed it. Moreover, docetaxel injection increased levels of TNF-α and IL-6 in plasma and expressions of phospho-NF-κB and phospho-STAT3 in both of lumbar spinal cord and sciatic nerves, while SH003 treatment inhibited those changes. Taken together, it is worth noting that TNF-α and IL-6 in plasma and phospho-NF-κB and phospho-STAT3 in spinal cord and sciatic nerves are putative biomarkers of docetaxel-induced peripheral neuropathy (DIPN) in mouse models. In addition, we suggest that SH003 would be beneficial for alleviation of docetaxel-induced neuropathic pain.

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Long noncoding RNA GAS5 ameliorates chronic constriction injury induced neuropathic pain in rats by modulation of the miR-452-5p/CELF2 axis

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0036 ◽

2020 ◽

Vol 98 (12) ◽

pp. 870-877

Author(s):

Yingjie Tian ◽

Li Sun ◽

Tao Qi

Keyword(s):

Nervous System ◽

Neuropathic Pain ◽

Noncoding Rna ◽

Chronic Constriction Injury ◽

Pain Treatment ◽

Thermal Hyperalgesia ◽

Spontaneous Pain ◽

Downstream Target ◽

Tnf Α ◽

The Central Nervous System

Neuropathic pain is a type of spontaneous pain that causes damage to the central nervous system. Long noncoding RNAs (lncRNAs) participate in the progression of various nervous system diseases, including neuropathic pain. However, the biological function of GAS5 in neuropathic pain remains unclear. Our findings revealed that GAS5 was downregulated in chronic constriction injury (CCI) rats. Besides, ELISA showed that the concentration of IL‐6, TNF-α, and IL‐1β were reduced by overexpressed GAS5 in spinal cord homogenates of CCI rats. Moreover, mechanical allodynia and thermal hyperalgesia in CCI rats were inhibited by GAS5 overexpression, suggesting that GAS5 overexpression attenuated neuropathic pain. Subsequently, we found that GAS5 served as a sponge for miR-452-5p in CCI rats and CELF2 was the downstream target of miR-452-5p. Finally, through a rescue assay, we found that GAS5 ameliorated neuropathic pain in CCI rats by sponging miR-452-5p to regulate CELF2 expression. Our study confirmed that GAS5 ameliorated neuropathic pain in rats by modulation of the miR-452-5p/CELF2 axis, which may provide some clues for neuropathic pain treatment.

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