scholarly journals Inhibitory Effects of Palmatine on P2X7 Receptor Expression in Trigeminal Ganglion and Facial Pain in Trigeminal Neuralgia Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Cancan Yin ◽  
Wenhao Shen ◽  
Mingming Zhang ◽  
Lequan Wen ◽  
Ruoyu Huang ◽  
...  
Keyword(s):  
Trigeminal Neuralgia ◽  
Trigeminal Ganglion ◽  
P2x7 Receptor ◽  
Facial Pain ◽  
Pain Threshold ◽  
Receptor Expression ◽  
Infraorbital Nerve ◽  
Distribution Area ◽  
Tnf Α ◽  
Mechanical Pain Threshold

Trigeminal Neuralgia (TN) refers to recurrent severe paroxysmal pain in the distribution area of the trigeminal nerve, which seriously affects the quality of life of patients. This research applied the chronic constriction injury of the infraorbital nerve (CCI—ION) approach to induce an animal model of TN in rats. The mechanical pain threshold of each group of rats was determined postoperatively; the expression of P2X7 receptor in trigeminal ganglion (TG) was assessed by qRT-PCR, immunofluorescence and Western blot; and the changes of the proinflammatory cytokines IL-1β and TNF-α in serum of rats were detected by ELISA. The results showed that the administration of palmatine in the TN rats could reduce the mechanical pain threshold, significantly decrease the expression of P2X7 receptor in TG, and lower the serum concentrations of IL-1β and TNF-α, compared to the sham group. In addition, the phosphorylation level of p38 in TG of TN rats was significantly decreased after treatment with palmatine. Likewise, inhibition of P2X7 expression by shRNA treatment could effectively counteract the adversary changes of pain sensitivity, IL-1β and TNF-α production, and p38 phosphorylation in TN rats. Our data suggest that palmatine may alleviate mechanical facial pain in TN rats possibly by reducing the expression of P2X7 receptor in TG of TN rats, which may be attributable to inhibiting p38 phosphorylation and reducing the release of IL-1β and TNF-α.

scholarly journals c-Abl-p38α signaling pathway mediates dopamine neuron loss in trigeminal neuralgia

2020 ◽  
Vol 16 ◽  
pp. 174480692093085 ◽  
Author(s):  
Jia Fu ◽  
Guo Mu ◽  
Ling Qiu ◽  
Jiaomei Zhao ◽  
Cehua Ou
Keyword(s):  
Trigeminal Neuralgia ◽  
Signaling Pathway ◽  
Dopaminergic Neurons ◽  
Pain Threshold ◽  
Kinase Inhibitor ◽  
Dopamine Neurons ◽  
Infraorbital Nerve ◽  
Neuron Death ◽  
Nonreceptor Tyrosine Kinase ◽  
Mechanical Pain Threshold

Trigeminal neuralgia is a common neuropathic pain in the head and face. The pathogenesis of trigeminal neuralgia is complex, and so far, the pathogenesis of trigeminal neuralgia involving peripheral and central nervous inflammation theory has not been explained clearly. The loss of dopamine neurons in striatum may play an important role in the development of trigeminal nerve, but the reason is not clear. C-Abl is a nonreceptor tyrosine kinase, which can be activated abnormally in the environment of neuroinflammation and cause neuron death. We found that in the rat model of infraorbital nerve ligation trigeminal neuralgia, the pain threshold decreased, the expression of c-Abl increased significantly, the downstream activation product p38 was also activated abnormally and the loss of dopamine neurons in striatum increased. When treated with imatinib mesylate (STI571), a specific c-Abl family kinase inhibitor, the p38 expression was decreased and the loss of dopaminergic neurons was reduced. The mechanical pain threshold of rats was also improved. In conclusion, c-abl-p38 signaling pathway may play an important role in the pathogenesis of trigeminal neuralgia, and it is one of the potential targets for the treatment of trigeminal neuralgia.

Preliminary study of calcium homeostasis modulator 1 involved in trigeminal neuralgia

2020 ◽  
Author(s):  
Yi Liu ◽  
Keji Li ◽  
Dong Huang ◽  
Xuebin Yan
Keyword(s):  
Trigeminal Neuralgia ◽  
Calcium Homeostasis ◽  
Pain Threshold ◽  
Sham Group ◽  
Ruthenium Red ◽  
Infraorbital Nerve ◽  
Control Group ◽  
Skin Area ◽  
Spinal Nucleus ◽  
Mechanical Pain Threshold

Abstract Background: The aim of this study was to observe the changes in the expression of calcium homeostasis modulator 1 (CALHM1) in the trigeminal nucleus of the trigeminal neuralgia (TN) rats with the infraorbital nerve-chronic constrictive nerve injury (ION-CCI) and to explore the role of CALHM1 in TN.Methods: Thirty SD rats were randomly assigned to 5 groups, namely normal control group (Control group), sham operation group (Sham group), TN model group (ION-CCI group), ruthenium red treatment group (RuR group) and control group of ruthenium red (NS group), with 6 rats in each group. An animal model was established by loosely ligating the rat's infraorbital nerve with a chrome gut in the ION-CCI group, while mice in the sham group were only exposed to the nerve and did not receive ligature. The rats in the RuR group were intraperitoneally injected with 0.5 mg/kg of CALHM1 inhibitor ruthenium red on the 9th day after the infraorbital nerve ligation, while the rats in NS group were intraperitoneally injected with an equal volume of normal saline on the 9th day after surgery. All experimental rats were tested for pain behavior 1 day before surgery, 1, 3, 5, 7, 9, 11 and 14 days after surgery, including the mechanical pain threshold of VonFrey filament in the trigeminal innervated skin area and number of faces captured in video recording. The expression of CALHM1 in the trigeminal spinal nucleus was detected on the 15th day after operation in all experimental groups.Results: The expression of CALHM1 in the trigeminal spinal nucleus of the ION-CCI group was significantly higher than that of control group and sham group on the 3rd and 15th day after modeling. The intraperitoneal injection of CALHM1 inhibitor ruthenium red increased the mechanical pain threshold of ION-CCI rats and significantly reduced the number of scratches, but did not change the expression of CALHM1 in the trigeminal spinal nucleus.Conclusion: The expression of CALHM1 protein in the trigeminal spinal nucleus is involved in the central sensitization of TN pain, which can be induced by elevated expression. Moreover, the hyperalgesia can be improved by using CALHM1 inhibitor.

scholarly journals Nav1.7 via Promotion of ERK in the Trigeminal Ganglion Plays an Important Role in the Induction of Pulpitis Inflammatory Pain

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Shukai Sun ◽  
Jiangxing Sun ◽  
Wenkai Jiang ◽  
Wei Wang ◽  
Longxing Ni
Keyword(s):  
Trigeminal Ganglion ◽  
Inflammatory Pain ◽  
Pain Threshold ◽  
Expression Levels ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Pulp Exposure ◽  
Mechanical Pain Threshold ◽  
Hematoxylin Eosin ◽  
Inhibitor Dose

The trigeminal ganglion (TG) refers to sensory neurons bodies that innervate the spinal cord and peripheral axons that innervate teeth. The tetrodotoxin-sensitive sodium (NA) channels (Nav1.7) play important roles in the pathophysiology of pain. In this study, we investigated the TG expression of Nav1.7 and extracellular signal-regulated kinase (ERK) in a rat model of pulpitis to explore the correlation between these channels and inflammatory pain. Pulpitis was confirmed by hematoxylin-eosin staining. In this study, we demonstrated that the reflex of rats to mechanical stimulation increases after pulp exposure and that the exposed rat molar pulp can upregulate the expression of Nav1.7 and ERK in the rat TG. Three days after rat pulp exposure, the expression levels of the two ion channels in the TG increased. TG target injection of PF04856264, a Nav1.7 inhibitor, dose-dependently increased the mechanical pain threshold and was able to inhibit ERK expression. TG target injection of PD98059, an ERK inhibitor, dose-dependently increased the mechanical pain threshold. These factors simultaneously resulted in the highest production. In this study, with the established link to inflammatory pain, we found that Nav1.7 and ERK both play important roles in the induction of inflammatory pain caused by pulpitis. We also found a correlation between the expression levels of Nav1.7 and ERK and the degree of inflammatory pain. Furthermore, ERK signaling pathways were promoted by the Nav1.7 in TG after pulpitis.

scholarly journals TLR8 in the trigeminal ganglion contributes to the maintenance of trigeminal neuropathic pain

2020 ◽  
Author(s):  
Lin-Xia Zhao ◽  
Xue-Qiang Bai ◽  
De-Li Cao ◽  
Xiao-Bo Wu ◽  
Ming Jiang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Trigeminal Ganglion ◽  
Proinflammatory Cytokines ◽  
Facial Pain ◽  
Calcium Concentration ◽  
Infraorbital Nerve ◽  
Rt Pcr ◽  
Pain Hypersensitivity ◽  
Trigeminal Neuropathic Pain ◽  
Significant Health

Abstract Background: Trigeminal neuropathic pain (TNP) is a significant health problem whereas the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) are recently demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. How TLR8 is expressed in the trigeminal ganglion (TG) after infraorbital nerve injury and whether TLR8 is involved in TNP have not been investigated.Methods: TNP model was established by the partial infraorbital nerve ligation (pIONL) in mice. The effect of TLR8 and its agonist VTX-2337 on pain hypersensitivity was checked by facial pain behavioral test. The immunostaining, real-time RT-PCR, and western blot were used to evaluate the expression of TLR8, pERK, pp38, and proinflammatory cytokines in the TG. The intracellular concentration of Ca 2+ was detected by the calcium imaging.Results: TLR8 was persistently increased in TG neurons in pIONL-induced TNP model. In addition, deletion of Tlr8 or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38, and decreased the expression of proinflammatory cytokines in the TG. Furthermore, intra-TG injection of TLR8 agonist VTX-2337 induced facial pain hypersensitivity. VTX-2337 also increased intracellular calcium concentration, induced activation of ERK and p38, and increased the proinflammatory cytokines expression in the TG.Conclusions: TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP.

scholarly journals The Up-regulation of TNF-α Maintains Trigeminal Neuralgia by Modulating MAPKs Phosphorylation and BKCa Channels in Trigeminal Nucleus Caudalis

2021 ◽  
Vol 15 ◽  
Author(s):  
Zhan-ying Lu ◽  
Juan Fan ◽  
Li-hua Yu ◽  
Bei Ma ◽  
Li-ming Cheng
Keyword(s):  
Neuropathic Pain ◽  
Trigeminal Neuralgia ◽  
Mechanical Allodynia ◽  
Infraorbital Nerve ◽  
Therapeutic Effects ◽  
Trigeminal Nucleus ◽  
Trigeminal Nucleus Caudalis ◽  
Tnf Α ◽  
Brain Ventricle ◽  
Cci Model

Trigeminal neuralgia (TN) is a severe chronic neuropathic pain. Despite numerous available medical interventions, the therapeutic effects are not ideal. To control the pain attacks, the need for more contemporary drugs continues to be a real challenge. Our previous study reported that Ca2+-activated K+ channels (BKCa) channels modulated by mitogen-activated protein kinases (MAPKs) in the trigeminal ganglia (TG) neurons play crucial roles in regulating TN, and some research studies demonstrated that inflammatory cytokine tumor necrosis factor alpha (TNF-α) could promote neuropathic pain. Meanwhile, the trigeminal nucleus caudalis (TNC), the first central site of the trigeminal nociceptive pathway, is responsible for processing sensory and pain signals from the peripheral orofacial area. Thus, this study is aimed to further investigate whether TNF-α and MAPKs phosphorylation in the TNC could mediate the pathogenesis of TN by modulating BKCa channels. The results showed that TNF-α of the TNC region is upregulated significantly in the chronic constriction injury of infraorbital nerve (ION-CCI) rats model, which displayed persistent facial mechanical allodynia. The normal rats with target injection of exogenous TNF-α to the fourth brain ventricle behaved just like the ION-CCI model rats, the orofacial mechanical pain threshold decreased clearly. Meanwhile, the exogenous TNF-α increased the action potential frequency and reduced the BKCa currents of TNC neurons significantly, which could be reversed by U0126 and SB203580, the inhibitors of MAPK. In addition, U0126, SB203580, and another MAPK inhibitor SP600125 could relieve the facial mechanical allodynia by being injected into the fourth brain ventricle of ION-CCI model rats, respectively. Taken together, our work suggests that the upregulation of TNF-α in the TNC region would cause the increase of MAPKs phosphorylation and then the negative regulation of BKCa channels, resulting in the TN.

scholarly journals Optogenetic stimulation of the motor cortex alleviates neuropathic pain in rats of infraorbital nerve injury with/without CGRP knock-down

2020 ◽  
Author(s):  
Jaisan Islam ◽  
Elina KC ◽  
Byeong Ho Oh ◽  
Soochong Kim ◽  
Sang-hwan Hyun ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Motor Cortex ◽  
Trigeminal Neuralgia ◽  
Trigeminal Ganglion ◽  
Primary Motor Cortex ◽  
Infraorbital Nerve ◽  
Motor Cortex Stimulation ◽  
Trigeminal Neuropathic Pain ◽  
Optogenetic Stimulation ◽  
Stimulation Of

Abstract Background Previous studies have reported that electrical stimulation of the motor cortex is effective in reducing trigeminal neuropathic pain; however, the effects of optical motor cortex stimulation remain unclear. Objective The present study aimed to investigate whether optical stimulation of the primary motor cortex can modulate chronic neuropathic pain in rats with infraorbital nerve constriction injury. Methods Animals were randomly divided into a trigeminal neuralgia group, a sham group, and a control group. Trigeminal neuropathic pain was generated via constriction of the infraorbital nerve and animals were treated via selective inhibition of calcitonin gene-related peptide in the trigeminal ganglion. We assessed alterations in behavioral responses in the pre-stimulation, stimulation, and post-stimulation conditions. In vivo extracellular recordings were obtained from the ventral posteromedial nucleus of the thalamus, and viral and α-CGRP expression were investigated in the primary motor cortex and trigeminal ganglion, respectively. Results We found that optogenetic stimulation significantly improved pain behaviors in the trigeminal neuralgia animals and it provided more significant improvement with inhibited α-CGRP state than active α-CGRP state. Electrophysiological recordings revealed decreases in abnormal thalamic firing during the stimulation-on condition. Conclusion Our findings suggest that optical motor cortex stimulation can alleviate pain behaviors in a rat model of trigeminal neuropathic pain. Transmission of trigeminal pain signals can be modulated via knock-down of α-CGRP and optical motor cortex stimulation.

scholarly journals The Effect and Possible Mechanism of Intradiscal Injection of Simvastatin in the Treatment of Discogenic Pain in Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Xiaodong Huang ◽  
Changkun Zheng ◽  
Weiheng Wang ◽  
Xiaojian Ye ◽  
Chia-Ying Lin ◽  
...  
Keyword(s):  
Pain Threshold ◽  
Intervertebral Disk ◽  
Control Group ◽  
Discogenic Pain ◽  
Intervertebral Disk Degeneration ◽  
Disk Degeneration ◽  
Tnf Α ◽  
Intradiscal Injection ◽  
Mechanical Pain Threshold ◽  
Cold Sensing

To study the effect of intradiscal injection of simvastatin on discogenic pain in rats and its possible mechanism, 30 adult female rats were used in this experiment. Twenty rats were randomly divided into sham operation group (Control group), intervertebral disk degeneration group (DDD group), intervertebral disk degeneration + hydrogel group (DDD + GEL group), and intervertebral disk degeneration + simvastatin group (DDD + SIM group). The mechanical pain threshold and cold sensation in rats were measured. The contents of NF-kappa B1, RelA, GAP43, SP, CGRP, TRPM 8, IL-1β, and TNF-α in the intervertebral disk (IVD), the corresponding contents of dorsal root ganglion (DRG) and plantar skin GAP43 and TRPM 8 were quantitatively detected by PCR. The corresponding IVDs were stained to detect their degeneration. There was no significant difference in the mechanical pain threshold between the groups at each time point. From the first day to the 8th week after surgery, the cold-sensing response of the DDD group was significantly higher than that of the Control group (P < 0.05). At 7 and 8 weeks postoperatively, the cold-sensing response of the DDD + SIM group was significantly lower than that of the DDD + GEL group (P < 0.05). The levels of NF-κB1, RelA, GAP43, SP, CGRP, TRPM8, IL-1β, and TNF-α in the IVD of DDD + SIM group were significantly lower than those in DDD group (P < 0.05). The content of GAP43 and TRPM8 in rat plantar skin decreased significantly and TRPM8 in DRG decreased significantly (P < 0.05).

scholarly journals Optogenetic Stimulation of The Motor Cortex Alleviates Neuropathic Pain in Rats of Infraorbital Nerve Injury With/Without CGRP Knock-Down

2020 ◽  
Author(s):  
Jaisan Islam ◽  
Elina KC ◽  
Byeong Ho Oh ◽  
Soochong Kim ◽  
Sang-hwan Hyun ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Motor Cortex ◽  
Trigeminal Neuralgia ◽  
Trigeminal Ganglion ◽  
Primary Motor Cortex ◽  
Infraorbital Nerve ◽  
Motor Cortex Stimulation ◽  
Trigeminal Neuropathic Pain ◽  
Optogenetic Stimulation ◽  
Stimulation Of

Abstract Background: Previous studies have reported that electrical stimulation of the motor cortex is effective in reducing trigeminal neuropathic pain; however, the effects of optical motor cortex stimulation remain unclear. Objective: The present study aimed to investigate whether optical stimulation of the primary motor cortex can modulate chronic neuropathic pain in rats with infraorbital nerve constriction injury.Methods: Animals were randomly divided into a trigeminal neuralgia group, a sham group, and a control group. Trigeminal neuropathic pain was generated via constriction of the infraorbital nerve and animals were treated via selective inhibition of calcitonin gene-related peptide in the trigeminal ganglion. We assessed alterations in behavioral responses in the pre-stimulation, stimulation, and post-stimulation conditions. In vivo extracellular recordings were obtained from the ventral posteromedial nucleus of the thalamus, and viral and α-CGRP expression were investigated in the primary motor cortex and trigeminal ganglion, respectively.Results: We found that optogenetic stimulation significantly improved pain behaviors in the trigeminal neuralgia animals and it provided more significant improvement with inhibited α-CGRP state than active α-CGRP state. Electrophysiological recordings revealed decreases in abnormal thalamic firing during the stimulation-on condition.Conclusion: Our findings suggest that optical motor cortex stimulation can alleviate pain behaviors in a rat model of trigeminal neuropathic pain. Transmission of trigeminal pain signals can be modulated via knock-down of α-CGRP and optical motor cortex stimulation.

scholarly journals Effects of long non-coding RNA Gm14461 on pain transmission in trigeminal neuralgia

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Mu Xu ◽  
Yi Yan ◽  
Mengye Zhu ◽  
Zhijian Wang ◽  
Xuexue Zhang ◽  
...  
Keyword(s):  
Trigeminal Neuralgia ◽  
Infraorbital Nerve ◽  
Mrna Levels ◽  
Protein Levels ◽  
Pain Transmission ◽  
Non Coding Rna ◽  
Tnf Α ◽  
Primary Mouse ◽  
Ganglion Neurons ◽  
Long Non Coding Rna

Abstract Background This study aims to investigate the role of long non-coding RNA Gm14461 in regulating pain transmission in trigeminal neuralgia (TN). The mouse TN model was produced by chronic constriction injury of the infraorbital nerve (CCI-ION). The values of mechanical withdrawal threshold (MWT) were measured to assess the nociception of mice at different times after CCI-ION surgery (0, 1, 3, 5, 7, 9, 11, 13, 15 d). The primary mouse trigeminal ganglion neurons (TGNs) were isolated from C57BL/6 J mice and treated with TNF-α to mimic a TN cellular model. The expression of Gm14461, TNF-α, IL-1β, and IL-6 was examined using qRT-PCR. The protein levels of CGRP and P2X3/7 receptor were measured using western blot. Results Gm14461 expression was increased in trigeminal ganglia (TGs) of TN mice on the operation side. Furthermore, Gm14461 knockdown in TGs increased, whereas Gm14461 overexpression decreased MWT in TN mice. Moreover, Gm14461 knockdown downregulated, whereas Gm14461 overexpression upregulated mRNA levels of TNF-α, IL-1β, and IL-6 and protein levels of CGRP and P2X3/7 receptor in TGs from TN mice. In vitro assay showed that Gm14461 was upregulated by TNF-α, IL-1β, and IL-6. Additionally, Gm14461 knockdown decreased protein levels of CGRP and P2X3/7 receptor in TNF-α-treated TGNs, whereas Gm14461 overexpression exerted the opposite effect. Conclusion Gm14461 promoted pain transmission (reduced MWT value) in a CCI-ION-induced mouse TN model. The underlying mechanisms might involve the regulation of pro-inflammatory cytokines, CGRP and P2X3/7 receptor.

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