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.

Neuronal disinhibition in the trigeminal nucleus caudalis in a model of chronic neuropathic pain

2010 ◽  
Vol 32 (3) ◽  
pp. 399-408 ◽  
Author(s):  
Yasmina B. Martin ◽  
Eduardo Malmierca ◽  
Carlos Avendaño ◽  
Angel Nuñez
Keyword(s):  
Neuropathic Pain ◽  
Trigeminal Nucleus ◽  
Chronic Neuropathic Pain ◽  
Trigeminal Nucleus Caudalis

1911 Distribution of c-fos expressing cells in the trigeminal nucleus caudalis following infraorbital nerve transection in the rat

1996 ◽  
Vol 25 ◽  
pp. S211
Author(s):  
Ryuji Teravama ◽  
Sumio Sakoda ◽  
Nahoko Nagamatsu ◽  
Tetsuva Ikeda ◽  
Toshikazu Nighimori
Keyword(s):  
Infraorbital Nerve ◽  
Nerve Transection ◽  
Trigeminal Nucleus ◽  
Trigeminal Nucleus Caudalis

Alleviation of trigeminal neuropathic pain by electroacupuncture: the role of hyperpolarization-activated cyclic nucleotide-gated channel protein expression in the Gasserian ganglion

2019 ◽  
Vol 37 (3) ◽  
pp. 192-198
Author(s):  
Liuyue Yang ◽  
Weihua Ding ◽  
Zerong You ◽  
Jinsheng Yang ◽  
Shiqian Shen ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Protein Expression ◽  
Cyclic Nucleotide ◽  
Mechanical Allodynia ◽  
Infraorbital Nerve ◽  
Gasserian Ganglion ◽  
Sprague Dawley ◽  
Trigeminal Neuropathic Pain ◽  
Sprague Dawley Rats ◽  
Gated Channel

Introduction: The aim of this study was to examine the effect of electroacupuncture (EA) on trigeminal neuropathic pain in rats and explore the potential mechanism underlying the putative therapeutic effect of EA. Methods: Trigeminal neuropathic pain behavior was induced in rats by unilateral chronic constriction injury of the distal infraorbital nerve (dIoN-CCI). EA was administered at ST2 ( Sibai) and Jiachengjiang. A total of 60 Sprague Dawley rats were divided into the following four groups ( n = 15 per group) to examine the behavioral outcomes after surgery and/or EA treatment: sham (no ligation); dIoN-CCI (received isoflurane only, without EA treatment); dIoN-CCI+EA-7d (received EA treatment for 7 days); and dIoN-CCI+EA-14d (received EA treatment for 14 days). Both evoked and spontaneous nociceptive behaviors were measured. Of these, 12 rats ( n = 4 from sham, dIoN-CCI, and dIoN-CCI+EA-14d groups, respectively) were used to analyze protein expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in the Gasserian ganglion (GG) by immunohistochemistry. Results: dIoN-CCI rats exhibited mechanical allodynia and increased face-grooming activity that lasted at least 35 days. EA treatment reduced mechanical allodynia and face-grooming in dIoN-CCI rats. Overall, 14 days of EA treatment produced a prolonged anti-nociceptive effect as compared to 7-day EA treatment. The counts of HCN1 and HCN2 immunopositive puncta were increased in the ipsilateral GG in dIoN-CCI rats and were reduced by 14 days of EA treatment. Discussion: EA treatment relieved trigeminal neuropathic pain in dIoN-CCI rats, and this effect was dependent on the duration of EA treatment. The downregulation of HCN expression may contribute to the anti-nociceptive effect of EA in this rat model of trigeminal neuropathic pain.

Excitation and inhibition of neurons in the trigeminal nucleus caudalis following periaqueductal gray stimulation

1978 ◽  
Vol 56 (1) ◽  
pp. 157-161 ◽  
Author(s):  
R. K. Andersen ◽  
J. P. Lund ◽  
E. Puil
Keyword(s):  
Periaqueductal Gray ◽  
Infraorbital Nerve ◽  
Reflex Response ◽  
Tooth Pulp ◽  
Trigeminal Nucleus ◽  
Trigeminal Nucleus Caudalis ◽  
Jaw Opening ◽  
Narcotic Analgesia ◽  
Jaw Opening Reflex ◽  
Decerebrate Cats

Electrical stimulation (3–4 shocks, 300 Hz, 30–150 μA) of the periaqueductal gray matter (CG) or dorsal raphé nucleus (DR) of decerebrate cats reduced or abolished the jaw-opening reflex response evoked by stimulation of either the tooth pulp or infraorbital nerve. In addition, CG or DR stimulation inhibited the response of 12 out of 16 trigeminal nucleus caudalis neurons to activation of their sensory afferent inputs. Ten other neurons recorded in the same sites, and often at the same time, but which did not respond to the sensory inputs utilized, were excited by identical stimuli to CG or DR. This excitatory response was blocked by intravenously administered naloxone (0.1–0.2 mg/kg). It is suggested that those neurons which are excited by CG and DR stimulation may be interneurons involved in pre- and post-synaptic inhibition of sensory transmission during stimulus-produced or narcotic analgesia.

scholarly journals Activation of microglial GLP-1R in the trigeminal nucleus caudalis suppresses central sensitization of chronic migraine after recurrent nitroglycerin stimulation

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Feng Jing ◽  
Qian Zou ◽  
Yangyang Wang ◽  
Zhiyou Cai ◽  
Yong Tang
Keyword(s):  
Chronic Migraine ◽  
Western Blotting ◽  
Central Sensitization ◽  
Microglial Activation ◽  
Morphological Changes ◽  
Trigeminal Nucleus ◽  
Trigeminal Nucleus Caudalis ◽  
Tnf Α

Abstract Background Central sensitization is considered a critical pathogenic mechanism of chronic migraine (CM). Activation of microglia in the trigeminal nucleus caudalis (TNC) contributes to this progression. Microglial glucagon-like peptide-1 receptor (GLP-1R) activation can alleviate pain; however, whether it is involved in the mechanism of CM has not been determined. Thus, this study aims to investigate the precise role of GLP-1R in the central sensitization of CM. Methods Repeated nitroglycerin injection-treated mice were used as a CM animal model in the experiment. To identify the distribution and cell localization of GLP-1R in the TNC, we performed immunofluorescence staining. Changes in the expression of GLP-1R, Iba-1, PI3K and p-Akt in the TNC were examined by western blotting. To confirm the effect of GLP-1R and PI3K/Akt in CM, a GLP-1R selective agonist (liraglutide) and antagonist (exendin(9–39)) and a PI3K selective antagonist (LY294002) were administered. Mechanical hypersensitivity was measured through von Frey filaments. To investigate the role of GLP-1R in central sensitization, calcitonin gene-related peptide (CGRP) and c-fos were determined using western blotting and immunofluorescence. To determine the changes in microglial activation, IL-1β and TNF-α were examined by western blotting, and the number and morphology of microglia were measured by immunofluorescence. We also confirmed the effect of GLP-1R on microglial activation in lipopolysaccharide-treated BV-2 microglia. Results The protein expression of GLP-1R was increased in the TNC after nitroglycerin injection. GLP-1R was colocalized with microglia and astrocytes in the TNC and was fully expressed in BV-2 microglia. The GLP-1R agonist liraglutide alleviated basal allodynia and suppressed the upregulation of CGRP, c-fos and PI3K/p-Akt in the TNC. Similarly, the PI3K inhibitor LY294002 prevented nitroglycerin-induced hyperalgesia. In addition, activating GLP-1R reduced Iba-1, IL-1β and TNF-α release and inhibited TNC microglial number and morphological changes (process retraction) following nitroglycerin administration. In vitro, the protein levels of IL-1β and TNF-α in lipopolysaccharide-stimulated BV-2 microglia were also decreased by liraglutide. Conclusions These findings suggest that microglial GLP-1R activation in the TNC may suppress the central sensitization of CM by regulating TNC microglial activation via the PI3K/Akt pathway.

EXTRACT OF WITHANIA SOMNIFERA ATTENUATES TIBIAL AND SURAL TRANSECTION INDUCED NEUROPATHIC PAIN

INDIAN DRUGS ◽  
2020 ◽  
Vol 57 (03) ◽  
pp. 27-36
Author(s):  
Tanmayee Amit Joshi ◽  
Pratima Arun Tatke
Keyword(s):  
Neuropathic Pain ◽  
Side Effects ◽  
Mechanical Allodynia ◽  
Biochemical Parameters ◽  
Plant Material ◽  
Withania Somnifera ◽  
Antioxidant Properties ◽  
Treatment Strategies ◽  
Potential Candidate ◽  
Tnf Α

Neuropathic pain can result from nerve injury, complication of diabetes, HIV infection and cancer. There are no defined guidelines for treatment and available treatments have often undesirable side effects. Hence, there is a adire need to develop treatment strategies which will be safe, effective and can be taken for prolonged time. Withania somnifera, a popular medicinal herb, has not been studied scientifically with respect to neuropathic pain. In this words plant material was extracted using various solvents. Neuropathic Pain was induced by Tibial and sural transection method. After induction, it resulted in development of chemical and heat evoked hyperalgesia, cold and mechanical allodynia. Rats treated with W. somnifera extract showed improvement in all pain related symptoms. Rats treated with extract showed improvement in biochemical parameters like production of superoxide ions, TBARs. myeloperoxidase and TNF-α. Anti inflammatory and antioxidant properties of extract could be responsible for these actions, hence it can be a potential candidate for treatment of neuropathic pain.

scholarly journals An Adapted Chronic Constriction Injury of the Sciatic Nerve Produces Sensory, Affective, and Cognitive Impairments: A Peripheral Mononeuropathy Model for the Study of Comorbid Neuropsychiatric Disorders Associated with Neuropathic Pain in Rats

Pain Medicine ◽  
2020 ◽  
Author(s):  
Priscila Medeiros ◽  
Ieda Regina dos Santos ◽  
Ivair Matias Júnior ◽  
Enza Palazzo ◽  
José Aparecido da Silva ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Anxiety And Depression ◽  
Novel Object Recognition ◽  
Walking Test ◽  
Cci Model ◽  
Underlying Mechanisms ◽  
Motor Alterations

Abstract Background Chronic constriction injury (CCI) is a model of neuropathic pain induced by four loose ligatures around the sciatic nerve. This work aimed to investigate the sensory, affective, cognitive, and motor changes induced by an adaptation of the CCI model by applying a single ligature around the sciatic nerve. Methods Mechanical allodynia was measured from day 1 to day 28 postsurgery by the von Frey test. The beam walking test (BWT) was conducted weekly until 28 days after surgery. Anxiety- and depression-like behaviors, and cognitive performance were assessed through the open field (OF), forced swimming (FS), and novel object recognition (NOR) tests, respectively, 21 days after surgery. Results The two CCI models, both Bennett and Xie’s model (four ligatures of the sciatic nerve) and a modification of it (one ligature), induced mechanical allodynia, increased immobility in the FS, and reduced recognition index in the NOR. The exploratory behavior and time spent in the central part of the arena decreased, while the defensive behavior increased in the OF. The animals subjected to the two CCI models showed motor alterations in the BWT; however, autotomy was observed only in the group with four ligatures and not in the group with a single ligature. Conclusions Overall these results demonstrate that our adapted CCI model, using a single ligature around the sciatic nerve, induces sensory, affective, cognitive, and motor alterations comparable to the CCI model with four ligatures without generating autotomy. This adaptation to the CCI model may therefore represent an appropriate and more easily performed model for inducing neuropathic pain and study underlying mechanisms and effective treatments.

scholarly journals TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice

2020 ◽  
Author(s):  
Lin-Xia Zhao ◽  
Ming Jiang ◽  
Xue-Qiang Bai ◽  
De-Li Cao ◽  
Xiao-Bo Wu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Inflammatory Cytokines ◽  
Trigeminal Ganglion ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Infraorbital Nerve ◽  
Trigeminal Neuropathic Pain ◽  
Intracellular Ca ◽  
Significant Health ◽  
Pro Inflammatory Cytokines

AbstractTrigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently been demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. Here, we show that TLR8 was persistently increased in the trigeminal ganglion (TG) neurons in model of TNP induced by partial infraorbital nerve ligation (pIONL). In addition, deletion or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38-MAPK, and decreased the expression of pro-inflammatory cytokines in the TG. Furthermore, intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity. VTX-2337 also increased the intracellular Ca2+ concentration, induced the activation of ERK and p38, and increased the expression of pro-inflammatory cytokines in the TG. These data indicate that 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 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.

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