scholarly journals Inhibition of TRPA1 and IL-6 Signal Alleviates Neuropathic Pain Following Chemotherapeutic Bortezomib

2019 ◽  
pp. 845-855 ◽  
Author(s):  
D. LIU ◽  
M. SUN ◽  
D. XU ◽  
X. MA ◽  
D. GAO ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Sensory Nerves ◽  
Cold Sensitivity ◽  
Systemic Injection

Bortezomib (BTZ) is used as a chemotherapeutic agent for the treatment of multiple myeloma. Nevertheless, one of the significant limiting complications of BTZ is painful peripheral neuropathy during BTZ therapy. Thus, in this study we examined signaling pathways of interleukin-6 (IL-6) and transient receptor potential ankyrin 1 (TRPA1) in the sensory nerves responsible for neuropathic pain induced by BTZ and further determined if influencing the pathways can improve neuropathic pain. ELISA and western blot analysis were used to examine the levels of IL-6, and IL-6 receptor (IL-6R), TRPA1 and p38-MAPK and JNK signal in the lumbar dorsal root ganglion. Behavioral test was performed to determine mechanical and cold sensitivity in a rat model. Our results showed that systemic injection of BTZ increased mechanical pain and cold sensitivity as compared with control animals. Data also showed that protein expression of TRPA1 and IL-6R was upregulated in the dorsal root ganglion of BTZ rats and blocking TRPA1 attenuated mechanical and cold sensitivity in control rats and BTZ rats. Notably, the inhibitory effect of blocking TRPA1 was smaller in BTZ rats than that in control rats. In addition, a blockade of IL-6 signal attenuated intracellular p38-MAPK and JNK in the sensory neuron. This also decreased TRPA1 expression and alleviated mechanical hyperalgesia and cold hypersensitivity in BTZ rats. In conclusion, we revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ, including IL-6-TRPA1, suggesting that blocking these signals is beneficial to alleviate neuropathic pain during BTZ intervention

scholarly journals The P2X7 Receptor Is Involved in Diabetic Neuropathic Pain Hypersensitivity Mediated by TRPV1 in the Rat Dorsal Root Ganglion

2021 ◽  
Vol 14 ◽  
Author(s):  
Anhui Wang ◽  
Xiangchao Shi ◽  
Ruoyang Yu ◽  
Bao Qiao ◽  
Runan Yang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Rat Model ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Intrathecal Injection ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Diabetic Neuropathic Pain ◽  
Satellite Glial Cells

The purinergic 2X7 (P2X7) receptor expressed in satellite glial cells (SGCs) is involved in the inflammatory response, and transient receptor potential vanilloid 1 (TRPV1) participates in the process of neurogenic inflammation, such as that in diabetic neuropathic pain (DNP) and peripheral neuralgia. The main purpose of this study was to explore the role of the P2X7 receptor in DNP hypersensitivity mediated by TRPV1 in the rat and its possible mechanism. A rat model of type 2 diabetes mellitus-related neuropathic pain (NPP) named the DNP rat model was established in this study. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of DNP rats were increased after intrathecal injection of the P2X7 receptor antagonist A438079, and the mRNA and protein levels of TRPV1 in the dorsal root ganglion (DRG) were decreased in DNP rats treated with A438079 compared to untreated DNP rats; in addition, A438079 also decreased the phosphorylation of p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) in the DNP group. Based on these results, the P2X7 receptor might be involved in DNP mediated by TRPV1.

scholarly journals Oxidized lipids and signaling pathways of G2A receptor involved in nerve injury induced neuropathic pain

2021 ◽  
Author(s):  
◽  
Tabea Osthues
Keyword(s):  
Neuropathic Pain ◽  
Signaling Pathways ◽  
Nerve Injury ◽  
Inflammatory Mediators ◽  
Pain Perception ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Wild Type ◽  
Injured Nerve

Neuropathic pain, a form of chronic pain, is a steadily rising health problem due to health costs and increasing numbers of patients. Neuropathic pain conditions arise upon metabolic disorders, infections, chemotherapeutic treatment, trauma or nerve injury. Especially nerve injury induced neuropathic pain is characterized by spontaneous or ongoing pain due to neuroimmune interactions. Thereby, inflammatory mediators, released by the injured nerve, recruit to and activate immune cells at the site of injury. Those mediators further activate transient receptor potential vanilloid 1 (TRPV1), a known channel involved in pain perception, or bind to G-protein coupled receptors (GPCR) in peripheral nerve endings. The following activated second messenger signaling pathways lead to sensitization of TRPV1. One of those GPCRs is G2A. The overall aim of this thesis was to investigate the role of G2A in nerve-injury induced neuropathic pain. For this, the common mouse model of nerve-injury induced neuropathic pain, the spared-nerve injury, was used. As measurements with dynamic plantar aesthesiometer showed, G2A-deficiency leads to reduced mechanical hypersensitivity. Upon analysis with FACS, ELISA and Luminex a reduced number of macrophages and neutrophils at the injured nerve, as well as less inflammatory mediators (TNFα, IL-6, VEGF) in G2A-deficient animals was observed. In dorsal root ganglia (DRGs) there was only a reduced number of macrophages and less IL-12 observed in G2A-deficient animals. Additionally, in wild-type mice, G2A agonist 9-HODE was elevated at the injured nerve, as a LC-MS/MS analysis showed. To investigate the underlying pathways of G2A-9-HODE signaling, a proteom screen was performed. This screen revealed upregulation of multiple proteins involved in migration in wild-type macrophages. Additionally, Ca-Imaging and transwell migration assays showed that the G2A antagonist G2A11, had desensitizing effects on DRG neurons and inhibited macrophage migration. Overall, the results suggest that loss of G2A has dual effects. On the one hand loss of G2A is antinociceptive. On the other hand, G2A-deficiency leads to reduced inflammation, suggesting G2A as promising target in treatment of neuropathic pain. Here, an antagonist had inhibitory effects on the migration and the sensitization.

scholarly journals Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 775
Author(s):  
Xingjuan Chen ◽  
Yaqian Duan ◽  
Ashley Riley ◽  
Megan Welch ◽  
Fletcher White ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Dorsal Root Ganglion ◽  
Patch Clamp ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Dorsal Root Ganglion Neurons ◽  
Transient Receptor Potential Vanilloid ◽  
Drg Neurons ◽  
Ganglion Neurons

Individuals with end-stage diabetic peripheral neuropathy present with decreased pain sensation. Transient receptor potential vanilloid type 1 (TRPV1) is implicated in pain signaling and resides on sensory dorsal root ganglion (DRG) neurons. We investigated the expression and functional activity of TRPV1 in DRG neurons of the Ins2+/Akita mouse at 9 months of diabetes using immunohistochemistry, live single cell calcium imaging, and whole-cell patch-clamp electrophysiology. 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence assay was used to determine the level of Reactive Oxygen Species (ROS) in DRGs. Although TRPV1 expressing neuron percentage was increased in Ins2+/Akita DRGs at 9 months of diabetes compared to control, capsaicin-induced Ca2+ influx was smaller in isolated Ins2+/Akita DRG neurons, indicating impaired TRPV1 function. Consistently, capsaicin-induced Ca2+ influx was decreased in control DRG neurons cultured in the presence of 25 mM glucose for seven days versus those cultured with 5.5 mM glucose. The high glucose environment increased cytoplasmic ROS accumulation in cultured DRG neurons. Patch-clamp recordings revealed that capsaicin-activated currents decayed faster in isolated Ins2+/Akita DRG neurons as compared to those in control neurons. We propose that in poorly controlled diabetes, the accelerated rate of capsaicin-sensitive TRPV1 current decay in DRG neurons decreases overall TRPV1 activity and contributes to peripheral neuropathy.

scholarly journals Development of Heat Hyperalgesia and Changes of TRPV1 and NGF Expression in Rat Dorsal Root Ganglion Following Joint Immobilization

2013 ◽  
pp. 215-219 ◽  
Author(s):  
T. NISHIGAMI ◽  
Y. OSAKO ◽  
M. IKEUCHI ◽  
K. YURI ◽  
T. USHIDA
Keyword(s):  
Dorsal Root Ganglion ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Wrist Joint ◽  
Receptor Potential ◽  
Phenotypic Change ◽  
Drg Neurons ◽  
Limb Immobilization ◽  
Heat Hyperalgesia

The aim of this study was to examine whether threshold to heat stimuli, and expression of transient receptor potential vanilloid1 (TRPV1) and nerve growth factor (NGF) in dorsal root ganglion (DRG) altered under conditions of long-term limb immobilization. A plastic cast was wrapped around the right limb from the forearm to the forepaw to keep wrist joint at 90° of flexion for 5 weeks. Heat hyperalgesia was tested using the plantar test at 6 h after removing cast. The rats were perfused transcardially with 4 % paraformaldehyde and DRGs were excised at 24 h after removing cast. For size distributions of the TRPV1-IR and NGF-IR neuronal profile, the DRG area measurements over 1000 DRG neurons per animal were measured in each side, on both the immobilized (ipsilateral) and contralateral sides. Ipsilateral withdrawal latency was significantly shorter than contralateral sides. Ipsilateral percentage of immunoreactive neurons in the total DRG neurons was significantly higher than contralateral sides in TRPV1-IR and NGF-IR. Long-term casting induced heat hyperalgesia, and up-regulation and phenotypic change of TRPV1-IR and NGF-IR in DRGs on the immobilized side. These DRG alterations may involve heat hyperalgesia after long-term limb immobilization.

scholarly journals Role of PAR2 in regulating oxaliplatin-induced neuropathic pain via TRPA1

2015 ◽  
Vol 6 (1) ◽  
pp. 111-116 ◽  
Author(s):  
Liujun Tian ◽  
Tianren Fan ◽  
Nan Zhou ◽  
Hui Guo ◽  
Weijie Zhang
Keyword(s):  
Neuropathic Pain ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cold Sensitivity ◽  
Downstream Signaling ◽  
Lumbar Dorsal Root Ganglion ◽  
Transient Receptor ◽  
Underlying Mechanisms ◽  
Cold Hypersensitivity

AbstractOxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors; however, one of the main limiting complications of OXL is neuropathic pain. In this study, the underlying mechanisms responsible for OXL evoked-neuropathic pain were examined. Using a rat model, the results demonstrated that intraperitoneal (i.p.) injection of OXL significantly increased mechanical pain and cold sensitivity as compared with control animals (P < 0.05 vs. control rats). Blocking proteinase-activated receptor 2 (PAR2) significantly attenuated mechanical pain and cold sensitivity observed in control rats and OXL rats (P < 0.05 vs. vehicle control). The attenuating effect of PAR2 on mechanical pain and cold sensitivity were significantly smaller in OXL-rats than in control rats. The role played by PAR2 downstream signaling pathways [namely, transient receptor potential ankyrin 1 (TRPA1)] in regulating OXL evoked-neuropathic pain was also examined. The data shows that TRPA1 expression was upregulated in the lumbar dorsal root ganglion (DRG) of OXL rats and blocking TRPA1 inhibited mechanical pain and heightened cold sensitivity (P <0.05 vs. control rats). Blocking PAR2 also significantly decreased TRPA1expression in the DRG. Findings in this study show that OXL intervention amplifies mechanical hyperalgesia and cold hypersensitivity and PAR2 plays an important role in regulating OXLinduced neuropathic pain via TRPA1 pathways.

scholarly journals Blocking TRPA1 and TNF-α Signal Improves Bortezomib-Induced Neuropathic Pain

2018 ◽  
Vol 51 (5) ◽  
pp. 2098-2110 ◽  
Author(s):  
Chunrui Li ◽  
Taoran Deng ◽  
Zhen Shang ◽  
Di Wang ◽  
Yi Xiao
Keyword(s):  
Neuropathic Pain ◽  
Tumor Necrosis Factor ◽  
Dorsal Root Ganglion ◽  
Dorsal Root ◽  
Tumor Necrosis ◽  
Cold Sensitivity ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

Background/Aims: Bortezomib (BTZ) is largely used as a chemotherapeutic agent for the treatment of multiple myeloma. However, one of the significant limiting complications of BTZ is painful peripheral neuropathy during BTZ therapy. The purpose of this study was to examine the underlying mechanisms leading to neuropathic pain induced by BTZ. Methods: ELISA and western blot analysis were used to examine the levels of tumor necrosis factor alpha (TNF-α) and its receptor, transient receptor potential ankyrin 1 (TRPA1) and intracellular p38-MAPK and JNK signal in the lumbar dorsal root ganglion. Behavioral test was performed to determine mechanical pain and cold sensitivity in a rat model. Results: Systemic injection of BTZ significantly increased mechanical pain and cold sensitivity as compared with control animals (P< 0.05 vs. control rats). Our data also showed that protein expression of TRPA1 was upregulated in the dorsal root ganglion of BTZ rats and blocking TRPA1 attenuated mechanical pain and cold sensitivity in control rats and BTZ rats (P< 0.05 vs. vehicle control). Notably, the inhibitory effect of blocking TRPA1 on mechanical pain and cold sensitivity was smaller in BTZ rats than that in control rats. In addition, a blockade of TNF-α attenuated intracellular p38-MAPK and JNK signal in the dorsal root ganglion. This also decreased TRPA1 expression and alleviated mechanical hyperalgesia and cold hypersensitivity in BTZ rats. Conclusion: We revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ. The data also suggest that blocking TRPA1 and tumor necrosis factor alpha is beneficial to alleviate neuropathic pain during BTZ intervention.

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