scholarly journals Dexmedetomidine Relieves Neuropathic Pain in Rats With Chronic Constriction Injury via the Keap1–Nrf2 Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Yatao Liu ◽  
Wei Liu ◽  
Xiao-Qing Wang ◽  
Zhan-Hai Wan ◽  
Yong-Qiang Liu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Rat Model ◽  
Chronic Constriction Injury ◽  
Tissue Injury ◽  
Quantitative Polymerase Chain Reaction ◽  
Immunohistochemical Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Spinal Cord Tissue ◽  
Antioxidant Genes

This study aimed to determine the role of dexmedetomidine (Dex) in neuropathic pain (NP) after chronic constriction injury (CCI) in a rat model as well as its underlying mechanism. First, a CCI rat model was established. After treatment with Dex, the severity of NP was ascertained by monitoring paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) at different time points. Immunohistochemical analysis was performed to determine the levels of Keap1 and Nrf2 in the spinal cord. Furthermore, the levels of Keap1–Nrf2–HO-1 pathway molecules, apoptotic proteins, and antioxidant genes in the spinal cord or isolated primary microglia were determined using quantitative polymerase chain reaction and western blotting. The release of proinflammatory cytokines was detected via enzyme-linked immunosorbent assay. To evaluate Dex-treated CCI-induced NP via the Keap1–Nrf2–HO-1 pathway, the rats were intrathecally injected with lentivirus to upregulate or downregulate the expression of Keap1. We found that Dex inhibited pathological changes and alleviated sciatic nerve pain as well as repressed inflammation, apoptosis, and redox disorders of the spinal cord in CCI rats. Keap1 protein expression was substantially downregulated, whereas Nrf2 and HO-1 expressions were significantly upregulated in the spinal cord after Dex administration. Additionally, Keap1 overexpression counteracted Dex-mediated inhibition of NP. Keap1 overexpression led to a decrease in Nrf2 and HO-1 levels as well as PWT and PWL but led to an aggravation of inflammation and antioxidant disorders and increased apoptosis. Keap1 silencing alleviated NP in rats with CCI, as evidenced by an increase in PWT and PWL. Keap1 depletion resulted in the alleviation of inflammation and spinal cord tissue injury in CCI rats. Collectively, these findings suggest that Dex inhibits the Keap1–Nrf2–HO-1-related antioxidant response, inflammation, and apoptosis, thereby alleviating NP in CCI rats.

Effect of Umbelliprenin on antinociceptive activity of morphine in a rat model of neuropathic pain induced by chronic constriction injury of the sciatic nerve

2020 ◽  
Vol 10 ◽  
Author(s):  
Samad Nazemi ◽  
Faranak Jafari ◽  
Bahareh Amin ◽  
Omid Gholami ◽  
Marzieh Kafami ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Rat Model ◽  
Chronic Constriction Injury ◽  
Antinociceptive Activity ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Male Wistar Rats ◽  
Anti Inflammatory

Objective: Although morphine is among of the first line medicines for treatment of neuropathic pain, evidence has shown that the morphine efficacy gradually decreases and a tolerance can occur. Rregarding the many reports concerning the antinociceptive and anti-inflammatory properties of umbelliprenin (UMB), this study aimed to investigate the effect of UMB on antinociceptive activity of morphine in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Methods: Twenty-four male Wistar rats were randomly divided into sham, CCI and CCI + UMB100 (100 μg UMB per rat) groups. UMB was intrathecally administered once daily for four consecutive days (from the day before surgery until the day 2 after surgery). All the animals received a single dose of morphine (5 mg/kg, s.c.) on day 14. To evaluate the effect of UMB on antinociceptive activity of morphine, allodynia and hyperalgesia were measured using the von-Frey and hot plate tests, before and 30 min after morphine injection, and the Percentage of Maximum Possible Effect (%MPE) was calculated. In addition, the expression and concentration of tumor necrosis factor-alpha (TNF-α), as a proinflammatory cytokine, was measured in the spinal cord using quantitative real-time PCR (RT-PCR) and ELISA, respectively. Key Findings: UMB significantly enhanced anti-allodynic and anti-hyperalgesic effects of morphine in the neuropathic animals. Moreover, UMB considerably downregulated TNF-α expression in the spinal cord of the animals. Conclusion: UMB can enhance antinociceptive effects of morphine, and this action may be due in part to its anti-inflammatory property.

scholarly journals Intrathecal Lentivirus-mediated Transfer of Interleukin-10 Attenuates Chronic Constriction Injury-induced Neuropathic Pain through Modulation of Spinal High-mobility Group Box 1 in Rats

2013 ◽  
Vol 5;16 (5;9) ◽  
pp. E615-E625
Author(s):  
Wangyuan Zou
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Rat Model ◽  
Inflammatory Markers ◽  
Chronic Constriction Injury ◽  
High Mobility ◽  
Interleukin 10 ◽  
High Mobility Group ◽  
Control Vector ◽  
Tnf Α

Background: Neuropathic pain is a complex state of chronic pain that is usually accompanied by peripheral and central nervous system damage or dysfunction. Previous studies have indicated that neuroinflammation in the spinal cord is an important contributor to neuropathological and behavioral abnormalities. A series of early inflammatory markers, such as IL-1, TNF-α, and IFN-γ, and advanced inflammatory markers, such as high-mobility group box 1 (HMGB1), are involved in neuroinflammation. Study Design: A randomized, double blind, controlled animal trial. Objective: In this study, a lentivirus delivering human IL-10 (LV/hIL-10) was administered intrathecally to determine the effects of IL-10 on allodynia and hyperalgesia in a chronic constriction injury-induced (CCI) rat model of neuropathic pain. Methods: Sprague-Dawley rats weighting 260 - 320 g were randomly divided into 4 groups. Group Sham (Sham), Group CCI±Normal Saline (NS), Group CCI±LV/hIL-10 (LV/hIL-10), and Group CCI±LV/control (vector). Rats in each group were intrathecally administered NS, LV/control, or recombinant vector LV/hIL-10 in a total volume of 10 μl. Paw withdrawal mechanical thresholds (PWMT) and paw withdrawal thermal latency PWTL were measured one day before CCI (baseline) and 0, 3, 7, 14, and 28 days after intrathecal administration. Cerebrospinal fluid (CSF) samples were collected during surgical plane anesthesia and the collected CSF samples were used to assay for human IL-10, rat IL-1β, rat IL-6, and rat TNF-α by enzyme-linked immunosorbent assay (ELISA). Animals were sacrificed and the L4-5 lumbar segment of the spinal cord was removed for determination of green fluorescent protein (GFP) expression. Immunohistochemical analysis was performed using anti HMGB1 antibodies and the expression of HMGB1 protein in the spinal cord was determined by Western blot analysis after intrathecal delivery (n = 8 each). Results: The results show that intrathecal LV/hIL-10 reverses enhanced pain states. Moreover, the increased level of HMGB1 exhibited in a late stage of CCI was inhibited by exogenous overexpression of hIL-10 in the CCI model. Expression of HMGB1, RAGE, and pAkt were lower in CCI-induced rats treated with LV/hIL-10 than in those treated with LV/control (vector) or saline (NS). Our results showed that IL-10 inhibits activation of the inflammatory HMGB1-RAGE pathway in the CCI rat model. Limitations: Further experimental investigations are needed to clarify the specific biological roles played by HMGB1 in IL-10-mediated regulation of neuropathic pain. Conclusion: Our results indicate that intrathecal lentiviral-mediated transfer of IL-10 attenuates CCI-induced neuropathic pain in rats. The anti-thermal hyperalgesia and anti-mechanical allodynia may be partly attributable to the decreased expression of HMGB1 and inhibition of HMGB1-RAGE pathway. Key words: Analgesia, interleukin-10, lentiviral, HMGB1, intrathecal, randomized, controlled trial

scholarly journals MiR-1906 attenuates neuropathic pain in rats by regulating the TLR4/mTOR/ Akt signaling pathway

2019 ◽  
Vol 10 (1) ◽  
pp. 175-179 ◽  
Author(s):  
Xianhai Fang ◽  
Huacheng Zhou ◽  
Shaopeng Huang ◽  
Jinfeng Liu
Keyword(s):  
Neuropathic Pain ◽  
Western Blotting ◽  
Rat Model ◽  
Latency Period ◽  
Enzyme Linked Immunosorbent Assay ◽  
Withdrawal Latency ◽  
Proinflammatory Mediators ◽  
Neuropathic Pain Model ◽  
Pathway Regulation

Abstract Background This study determined the role of miR-1906 in neuropathic pain and proliferation in neuronal cells using a chronic constriction injury (CCI)-induced neuropathic pain (NP) rat model. Methodology NP was induced by CCI. Animals were divided into a sham group, an NP group, and a miR-1906 mimic group, which received 500 nmol/kg of a miR-1906 mimic intrathecally for 10 consecutive days following surgery. The effect of miR-1906 agomir was determined by estimating the thermal and mechanical withdrawal latency; an enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of proinflammatory mediators. Western blotting and reverse-transcription polymerase chain reaction (RT-PCR) were used to determine protein expression in the spinal tissues of the CCI-induced neuropathic pain rat model. Results Administration of miR-1906 agomir increased the mechanical and thermal withdrawal latency period and the levels of inflammatory mediators compared with the NP group. Western blotting showed that treatment with miR-1906 agomir attenuated the levels of Akt, mTOR, TLR-4, and PI3K proteins in the spinal tissues of the CCI-induced neuropathic pain model. TLR-4 and NF-κB gene expression was lower in the miR-1906 agomir group than in the NP group. Conclusion miR-1906 gene stimulation reduced neuropathic pain by enhancing Akt/nTOR/PI3K and TLR-4/NF-κB pathway regulation.

scholarly journals Haematoxylon campechianum Extract Ameliorates Neuropathic Pain via Inhibition of NF-κB/TNF-α/NOX/iNOS Signalling Pathway in a Rat Model of Chronic Constriction Injury

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 386 ◽  
Author(s):  
Mansour Sobeh ◽  
Mona F. Mahmoud ◽  
Samar Rezq ◽  
Mohamed A.O. Abdelfattah ◽  
Islam Mostafa ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Brain Stem ◽  
Rat Model ◽  
Structural Changes ◽  
Chronic Constriction Injury ◽  
Biological Activities ◽  
Ethanol Extract ◽  
Phenolic Constituents ◽  
Anti Inflammatory

In this study, the phytochemical composition and the possible prophylactic effects of an aqueous ethanol extract of Haematoxylon campechianum flowers (HCF) on peripheral neuropathic pain in a chronic constriction injury (CCI) rat model are investigated. Rats with induced CCI were subjected to neuropathic pain behaviour tests and evaluated by chemical, thermal, and mechanical sensation tests and functional recovery of the brain stem and sciatic nerve at 7- and 14-day intervals. The effect of the extract on acute pain and inflammation is also investigated. The extract exerted both peripheral and central analgesic and anti-inflammatory properties in addition to antipyretic effects that are clear from targeting COX, LOX and PGE. It was found that CCI produced significant thermal and mechanical hyperalgesia, cold allodynia and deleterious structural changes in both sciatic nerve and brain stem. Treatments with HCF extract significantly improved cold and thermal withdrawal latency, mechanical sensibility and ameliorated deleterious changes of sciatic nerve and brain stem at different dose levels. The extract also ameliorated oxidative stress and inflammatory markers in brain stem and sciatic nerve. It suppressed the apoptotic marker, p53, and restored myelin sheath integrity. The effects of HCF extract were more potent than pregabalin. Fifteen secondary metabolites, mainly gallotannins and flavonoids, were characterized in the extract based on their retention times and MS/MS data. The identified phenolic constituents from the extract could be promising candidates to treat neuropathic pain due to their diverse biological activities, including antioxidant, anti-inflammatory and neuroprotective properties.

Lidocaine activates autophagy of astrocytes and ameliorates chronic constriction injury-induced neuropathic pain

2020 ◽  
Author(s):  
Jiaqi Yuan ◽  
Yue Fei
Keyword(s):  
Cell Proliferation ◽  
Neuropathic Pain ◽  
Chronic Constriction Injury ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammatory Factor ◽  
Experimental Basis ◽  
Withdrawal Threshold ◽  
Withdrawal Latency ◽  
Tnf Α ◽  
Rat Astrocytes

Abstract Lidocaine is a commonly used drug to alleviate neuropathic pain (NP). This work aims to investigate the mechanism of lidocaine in alleviating NP. Chronic constriction injury (CCI) rats were established by surgery to induce NP. We observed the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of rats. Immunofluorescence staining was performed to determine the LC3/glial fibrillary acidic protein (GFAP)-positive cells. Rat astrocytes were treated with lipopolysaccharide (LPS) to induce CCI, and then treated with lidocaine or 3-MA (autophagy inhibitor). CCK-8 was performed to detect cell proliferation. Western blot and enzyme-linked immunosorbent assay were performed to detect the level of protein and inflammatory factor. CCI rats exhibited a decrease of MWT and TWL, which was effectively abolished by lidocaine. Lidocaine enhanced the number of LC3/GFAP-positive cells in CCI rats. Moreover, lidocaine inhibited the expression of GFAP and p62, and enhanced LC3-II/LC3-I expression in the LPS-treated astrocytes. Lidocaine inhibited the level of TNF-α and IL-1β in the LPS-treated astrocytes. The influence conferred by lidocaine was effectively abolished by 3-MA. In conclusion, our work demonstrates that lidocaine activates autophagy of astrocytes and ameliorates CCI-induced NP. Thus, our study provides a further experimental basis for the mechanism of lidocaine to alleviate NP.

scholarly journals Mild Moxibustion Decreases the Expression of Prokineticin 2 and Prokineticin Receptor 2 in the Colon and Spinal Cord of Rats with Irritable Bowel Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Cili Zhou ◽  
Jimeng Zhao ◽  
Luyi Wu ◽  
Renjia Huang ◽  
Yin Shi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Irritable Bowel Syndrome ◽  
Rat Model ◽  
Rat Colon ◽  
Spinal Cord Tissue ◽  
Model Group ◽  
Colorectal Distension ◽  
Prokineticin 2 ◽  
Mild Moxibustion ◽  
Irritable Bowel

It has been proven that prokineticin 2 (PK2) and its receptor PKR2 play an important role in hyperalgesia, while mild moxibustion can relieve visceral hypersensitivity in a rat model of irritable bowel syndrome (IBS). The goal of the present study was to determine the effects of mild moxibustion on the expression of PK2 and PKR2 in colon and spinal cord in IBS rat model, which was induced by colorectal distension using inflatable balloons. After mild moxibustion treatment, abdominal withdrawal reflex (AWR) scores were assessed by colorectal distension; protein and mRNA expression of PK2 and PKR2 in rat colon and spinal cord was determined by immunohistochemistry and fluorescence quantitative PCR. Compared with normal rats, the AWR scores of rats and the expressions of PK2/PKR2 proteins and mRNAs in colon and spinal cord tissue were significantly increased in the model group; compared with the model group, the AWR scores of rats and the expressions of PK2/PKR2 proteins and mRNAs in colon and spinal cord tissue were significantly decreased in the mild moxibustion group. These findings suggest that the analgesia effect of mild moxibustion may be associated with the reduction of the abnormally increased expression of the PK2/PKR2 proteins and mRNAs in the colon and spinal cord.

scholarly journals Piezo2 expression in the spinal cord of neuropathic pain rat model

IBRO Reports ◽  
2019 ◽  
Vol 6 ◽  
pp. S293-S294
Author(s):  
Pham Thuy Linh ◽  
Juhee Shin ◽  
Yin Yu Hua ◽  
Hyo Jung Shin ◽  
Nara Shin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Rat Model
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