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 P2X3 receptor expression in dorsal horn of spinal cord and pain threshold after estrogen therapy for prevention therapy in neuropathic pain

2020 ◽  
Vol 60 ◽  
pp. 389-395
Author(s):  
Rohadi Muhammad Rosyidi ◽  
Bambang Priyanto ◽  
Dewa Putu Wisnu Wardhana ◽  
Krisna Tsaniadi Prihastomo ◽  
Syauq Hikmi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Pain Threshold ◽  
Estrogen Therapy ◽  
Receptor Expression ◽  
P2x3 Receptor ◽  
Prevention Therapy

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.

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 SUR1, newly expressed in astrocytes, mediates neuropathic pain in a mouse model of peripheral nerve injury

2021 ◽  
Vol 17 ◽  
pp. 174480692110066
Author(s):  
Orest Tsymbalyuk ◽  
Volodymyr Gerzanich ◽  
Aaida Mumtaz ◽  
Sanketh Andhavarapu ◽  
Svetlana Ivanova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Thermal Sensitivity ◽  
Gradual Improvement ◽  
Pain Behaviors

Background Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL -6 ), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. Methods Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. Results Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. Conclusion SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

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

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.

scholarly journals Role of the immune system in neuropathic pain

2019 ◽  
Vol 20 (1) ◽  
pp. 33-37 ◽  
Author(s):  
Marzia Malcangio
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Nervous System ◽  
Neuropathic Pain ◽  
Immune System ◽  
Peripheral Nerve ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Immune Cells ◽  
Peripheral Nerve Injury

AbstractBackgroundAcute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia).Critical role for immune system cells in chronic painPreclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain.Immune system reactions to peripheral nerve injuriesAt the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG.Immune system mechanisms in the central nervous systemIn the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms.Conclusions and implicationsDefinition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.

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