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

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.

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

10.21203/rs.2.24451/v1 ◽

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.

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Preventing oxaliplatin‑induced neuropathic pain: Using berberine to inhibit the activation of NF‑κB and release of pro‑inflammatory cytokines in dorsal root ganglions in rats

Experimental and Therapeutic Medicine ◽

10.3892/etm.2020.9567 ◽

2020 ◽

Vol 21 (2) ◽

Author(s):

Wan Ni ◽

Xiaolan Zheng ◽

Ling Hu ◽

Chao Kong ◽

Qingbang Xu

Keyword(s):

Neuropathic Pain ◽

Inflammatory Cytokines ◽

Dorsal Root ◽

Dorsal Root Ganglions ◽

Pro Inflammatory Cytokines

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

Acupuncture in Medicine ◽

10.1177/0964528419841614 ◽

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.

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Pulsed radiofrequency to the dorsal root ganglion or the sciatic nerve reduces neuropathic pain behavior, decreases peripheral pro-inflammatory cytokines and spinal β-catenin in chronic constriction injury rats

Regional Anesthesia and Pain Medicine ◽

10.1136/rapm-2018-100032 ◽

2019 ◽

Vol 44 (7) ◽

pp. 742-746 ◽

Cited By ~ 2

Author(s):

Ren Jiang ◽

Ping Li ◽

Yong-Xing Yao ◽

Hong Li ◽

Rongjun Liu ◽

...

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Dorsal Root Ganglion ◽

Inflammatory Cytokines ◽

Dorsal Root ◽

Chronic Constriction Injury ◽

Pain Behavior ◽

Pulsed Radiofrequency ◽

Behavioral Tests ◽

Pro Inflammatory Cytokines

Background and objectivesPulsed radiofrequency (PRF) is a minimal neurodestructive interventional pain therapy. However, its analgesic mechanism remains largely unclear. We aimed to investigate the peripheral and spinal mechanisms of PRF applied either adjacent to the ipsilateral L5 dorsal root ganglion (PRF-DRG) or PRF to the sciatic nerve (PRF-SN) in the neuropathic pain behavior induced by chronic constriction injury (CCI) in rats.MethodsOn day 0, CCI or sham surgeries were performed. Rats then received either PRF-DRG, PRF-SN, or sham PRF treatment on day 4. Pain behavioral tests were conducted before surgeries and on days 1, 3, 5, 7, 9, 11, 13, and 14. After the behavioral tests, the rats were sacrificed. The venous blood or sciatic nerve samples were collected for ELISAs and the dorsal horns of the L4–L6 spinal cord were collected for western blot examination.ResultsThe mechanical allodynia and the thermal hyperalgesia has been relieved by a single PRF-DRG or PRF-SN application. In addition, the analgesic effect of PRF-DRG was superior to PRF-SN on CCI-induced neuropathic pain. Either PRF-DRG or PRF-SN reversed the enhancement of interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) levels in the blood of CCI rats. PRF-DRG or PRF-SN also downregulated spinal β-catenin expression.ConclusionsPRF treatment either to DRG or to sciatic nerve reduced neuropathic pain behavior, and reduced peripheral levels of pro-inflammatory cytokines and spinal β-catenin expression in CCI rats. PRF to DRG has a better analgesic effect than PRF to the nerve.

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

10.21203/rs.3.rs-48555/v2 ◽

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

10.21203/rs.3.rs-48555/v1 ◽

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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Antagonism of Transient Receptor Potential Ankyrin Type-1 Channels as a Potential Target for the Treatment of Trigeminal Neuropathic Pain: Study in an Animal Model

International Journal of Molecular Sciences ◽

10.3390/ijms19113320 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3320 ◽

Cited By ~ 10

Author(s):

Chiara Demartini ◽

Rosaria Greco ◽

Anna Zanaboni ◽

Oscar Francesconi ◽

Cristina Nativi ◽

...

Keyword(s):

Gene Expression ◽

Neuropathic Pain ◽

Mechanical Allodynia ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Infraorbital Nerve ◽

Trigeminal Neuropathic Pain ◽

Trpv1 Channels ◽

Transient Receptor

Transient receptor potential ankyrin type-1 (TRPA1) channels are known to actively participate in different pain conditions, including trigeminal neuropathic pain, whose clinical treatment is still unsatisfactory. The aim of this study was to evaluate the involvement of TRPA1 channels by means of the antagonist ADM_12 in trigeminal neuropathic pain, in order to identify possible therapeutic targets. A single treatment of ADM_12 in rats 4 weeks after the chronic constriction injury of the infraorbital nerve (IoN-CCI) significantly reduced the mechanical allodynia induced in the IoN-CCI rats. Additionally, ADM_12 was able to abolish the increased levels of TRPA1, calcitonin gene-related peptide (CGRP), substance P (SP), and cytokines gene expression in trigeminal ganglia, cervical spinal cord, and medulla induced in the IoN-CCI rats. By contrast, no significant differences between groups were seen as regards CGRP and SP protein expression in the pars caudalis of the spinal nucleus of the trigeminal nerve. ADM_12 also reduced TRP vanilloid type-1 (TRPV1) gene expression in the same areas after IoN-CCI. Our findings show the involvement of both TRPA1 and TRPV1 channels in trigeminal neuropathic pain, and in particular, in trigeminal mechanical allodynia. Furthermore, they provide grounds for the use of ADM_12 in the treatment of trigeminal neuropathic pain.

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Trigeminal Nerve Injury ErbB3/ErbB2 Promotes Mechanical Hypersensitivity

Anesthesiology ◽

10.1097/aln.0b013e3182604b2b ◽

2012 ◽

Vol 117 (2) ◽

pp. 381-388 ◽

Cited By ~ 7

Author(s):

Fei Ma ◽

Liping Zhang ◽

Karin N. Westlund

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Mechanical Allodynia ◽

Infraorbital Nerve ◽

Wild Type ◽

Transgenic Rats ◽

Neuregulin 1 ◽

Mechanical Hypersensitivity ◽

Trigeminal Neuropathic Pain ◽

Whisker Pad

Background Chronic constriction injury of the trigeminal infraorbital nerve results in transient analgesia followed by whisker pad mechanical allodynia in rats. Neuregulin 1 expressed on axonal membranes binds receptor tyrosine kinase ErbB, promoting Schwann cell development and remyelination. This study investigated whether orofacial mechanical allodynia is signaled by ErbB3-ErbB2 heterodimers in injured nerves. Methods Whisker pad mechanical allodynia (von Frey stimuli) was quantified in wild type rats and in transgenic rats with Sleeping Beauty transposon mutation for neuregulin 1 transgene. Pain-related behavior was retested after intraperitoneal injection of the ErbB2 inhibitor Lapatinib, an agent shown by others to reduce breast cancer pain. Infraorbital nerve injury was evaluated histologically with myelin and neuronal biomarkers. ErbB3 changes over time were measured with western blots. Results Whisker pad mechanical hypersensitivity began in week 2 in wild type rats (3.11 ± 5.93 g vs. 18.72 ± 0.00 g after sham surgery, n = 9, P < 0.001), indicating trigeminal neuropathic pain, but was not evident in transgenic rats (odds ratio: 1.12, 95% confidence interval: 0.38-3.35). Initiation of statistically significant mechanohypersensitivity was delayed until week 6 after surgery in transgenic rats (3.44 ± 4.60 g vs. 18.72 ± 0.00 g, n = 4, P < 0.001). Mechanical allodynia, which persisted 8 weeks in wild type rats was alleviated by Lapatinib (15 ± 3.89 g vs. 2.45 ± 1.13 g, n = 6, P < 0.001). Infraorbital nerve damage was verified histologically. Statistically significant ErbB3 increases (weeks 5 and 10) in wild type and transgenic rats (week 10) coincided with time points when mechanical hypersensitivity was present. Conclusion The Neuregulin 1-ErbB3-ErbB2 complex is a causal mechanism in nerve injury-induced trigeminal neuropathic pain. Understanding peripheral glial mechanisms after nerve injury will improve neuropathic pain treatment.

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