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

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.

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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 ◽

10.3390/biom10030386 ◽

2020 ◽

Vol 10 (3) ◽

pp. 386 ◽

Cited By ~ 3

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.

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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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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

January 2018 - Pain Physician ◽

10.36076/ppj.2013/16/e615 ◽

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

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.714996 ◽

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.

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1,3,4-Oxadiazole Derivative Attenuates Chronic Constriction Injury Induced Neuropathic Pain: A Computational, Behavioral, and Molecular Approach

Brain Sciences ◽

10.3390/brainsci10100731 ◽

2020 ◽

Vol 10 (10) ◽

pp. 731

Author(s):

Muhammad Faheem ◽

Syed Hussain Ali ◽

Abdul Waheed Khan ◽

Mahboob Alam ◽

Umair Ilyas ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Pain Perception ◽

Chronic Constriction Injury ◽

Neuroprotective Effect ◽

Underlying Mechanism ◽

Contributing Factors ◽

Neuroprotective Effects ◽

In Silico Studies

The production and up-regulation of inflammatory mediators are contributing factors for the development and maintenance of neuropathic pain. In the present study, the post-treatment of synthetic 1,3,4 oxadiazole derivative (B3) for its neuroprotective potential in chronic constriction injury-induced neuropathic pain was applied. In-silico studies were carried out through Auto Dock, PyRx, and DSV to obtain the possible binding and interactions of the ligands (B3) with COX-2, IL-6, and iNOS. The sciatic nerve of the anesthetized rat was constricted with sutures 3/0. Treatment with 1,3,4-oxadiazole derivative was started a day after surgery and continued until the 14th day. All behavioral studies were executed on day 0, 3rd, 7th, 10th, and 14th. The sciatic nerve and spinal cord were collected for further molecular analysis. The interactions in the form of hydrogen bonding stabilizes the ligand target complex. B3 showed three hydrogen bonds with IL-6. B3, in addition to correcting paw posture/deformation induced by CCI, attenuates hyperalgesia (p < 0.001) and allodynia (p < 0.001). B3 significantly raised the level of GST and GSH in both the sciatic nerve and spinal cord and reduced the LPO and iNOS (p < 0.001). B3 attenuates the pathological changes induced by nerve injury, which was confirmed by H&E staining and IHC examination. B3 down-regulates the over-expression of the inflammatory mediator IL-6 and hence provides neuroprotective effects in CCI-induced pain. The results demonstrate that B3 possess anti-nociceptive and anti-hyperalgesic effects and thus minimizes pain perception and inflammation. The possible underlying mechanism for the neuroprotective effect of B3 probably may be mediated through IL-6.

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Attenuating Effect of Portulaca oleracea Extract on Chronic Constriction Injury Induced Neuropathic Pain in Rats: An Evidence of Anti-oxidative and Anti-inflammatory Effects

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190314110528 ◽

2019 ◽

Vol 18 (4) ◽

pp. 342-349 ◽

Cited By ~ 2

Author(s):

Fatemeh Forouzanfar ◽

Hossein Hosseinzadeh ◽

Mohammad B. Khorrami ◽

Samira Asgharzade ◽

Hassan Rakhshandeh

Keyword(s):

Neuropathic Pain ◽

Chronic Constriction Injury ◽

Portulaca Oleracea ◽

Dependent Manner ◽

Tnf Α ◽

Antinociceptive Effects ◽

Drug Treatments ◽

Thiol Content ◽

Anti Inflammatory ◽

Dose Dependent

Background: Neuropathic pain responds poorly to drug treatments. The present study investigated the therapeutic effect of Portulaca oleracea, in chronic constriction injury (CCI)-induced neuropathic pain in rats. Objective & Methods: Neuropathic pain was performed by putting four loose ligatures around the sciatic nerve. CCI resulted in the development of heat hyperalgesia, mechanical allodynia and cold allodynia accompanied by an increase in the contents of TNF-α, IL1β, malondialdehyde, with a reduction in total thiol content. Results: Administration of Portulaca oleracea (100 and 200 mg/kg intraperitoneal) for 14 days in CCI rats significantly alleviated pain-related behaviors, oxidative damage and inflammatory cytokines in a dose-dependent manner. Conclusion: In conclusion, it is suggested that the antinociceptive effects of Portulaca oleracea might be due to antioxidant and anti-inflammatory properties.

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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

Brain Research ◽

10.1016/j.brainres.2012.02.033 ◽

2012 ◽

Vol 1450 ◽

pp. 24-32 ◽

Cited By ~ 10

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

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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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