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

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

2013 ◽  
Vol 110 (7) ◽  
pp. 1663-1671 ◽  
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.

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.

The thalidomide analgesic effect is associated with differential TNF-α receptor expression in the dorsal horn of the spinal cord as studied in a rat model of neuropathic pain

2012 ◽  
Vol 1450 ◽  
pp. 24-32 ◽  
Author(s):  
Pablo Andrade ◽  
Veerle Visser-Vandewalle ◽  
John S. Del Rosario ◽  
Marc A. Daemen ◽  
Wim A. Buurman ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Rat Model ◽  
Analgesic Effect ◽  
Receptor Expression ◽  
Tnf Α

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

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.

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

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1187
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

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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