Dataset Information

Estradiol upregulates voltage-gated sodium channel 1.7 in trigeminal ganglion contributing to hyperalgesia of inflamed TMJ.

ABSTRACT:

Background

Temporomandibular disorders (TMDs) have the highest prevalence in women of reproductive age. The role of estrogen in TMDs and especially in TMDs related pain is not fully elucidated. Voltage-gated sodium channel 1.7 (Nav1.7) plays a prominent role in pain perception and Nav1.7 in trigeminal ganglion (TG) is involved in the hyperalgesia of inflamed Temporomandibular joint (TMJ). Whether estrogen could upregulate trigeminal ganglionic Nav1.7 expression to enhance hyperalgesia of inflamed TMJ remains to be explored.

Methods

Estrous cycle and plasma levels of 17?-estradiol in female rats were evaluated with vaginal smear and enzyme linked immunosorbent assay, respectively. Female rats were ovariectomized and treated with 17?-estradiol at 0 ?g, 20 ?g and 80 ?g, respectively, for 10 days. TMJ inflammation was induced using complete Freund's adjuvant. Head withdrawal thresholds and food intake were measured to evaluate the TMJ nociceptive responses. The expression of Nav1.7 in TG was examined using real-time PCR and western blot. The activity of Nav1.7 promoter was examined using luciferase reporter assay. The locations of estrogen receptors (ER? and ER?), the G protein coupled estrogen receptor (GPR30), and Nav1.7 in TG were examined using immunohistofluorescence.

Results

Upregulation of Nav1.7 in TG and decrease in head withdrawal threshold were observed with the highest plasma 17?-estradiol in the proestrus of female rats. Ovariectomized rats treated with 80 ?g 17?-estradiol showed upregulation of Nav1.7 in TG and decrease in head withdrawal threshold as compared with that of the control or ovariectomized rats treated with 0 ?g or 20 ?g. Moreover, 17?-estradiol dose-dependently potentiated TMJ inflammation-induced upregulation of Nav1.7 in TG and also enhanced TMJ inflammation-induced decrease of head withdrawal threshold in ovariectomized rats. In addition, the estrogen receptor antagonist, ICI 182,780, partially blocked the 17?-estradiol effect on Nav1.7 expression and head withdrawal threshold in ovariectomized rats. ER? and ER?, but not GPR30, were mostly co-localized with Nav1.7 in neurons in TG. In the nerve growth factor-induced and ER?-transfected PC12 cells, 17?-estradiol dose-dependently enhanced Nav1.7 promoter activity, whereas mutations of the estrogen response element at -1269/-1282 and -1214/-1227 in the promoter completely abolished its effect on the promoter activity.

Conclusion

Estradiol could upregulate trigeminal ganglionic Nav1.7 expression to contribute to hyperalgesia of inflamed TMJ.

SUBMITTER: Bi RY

PROVIDER: S-EPMC5459440 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Estradiol upregulates voltage-gated sodium channel 1.7 in trigeminal ganglion contributing to hyperalgesia of inflamed TMJ.

Bi Rui-Yun RY Meng Zhen Z Zhang Peng P Wang Xue-Dong XD Ding Yun Y Gan Ye-Hua YH

PloS one 20170605 6

<h4>Background</h4>Temporomandibular disorders (TMDs) have the highest prevalence in women of reproductive age. The role of estrogen in TMDs and especially in TMDs related pain is not fully elucidated. Voltage-gated sodium channel 1.7 (Nav1.7) plays a prominent role in pain perception and Nav1.7 in trigeminal ganglion (TG) is involved in the hyperalgesia of inflamed Temporomandibular joint (TMJ). Whether estrogen could upregulate trigeminal ganglionic Nav1.7 expression to enhance hyperalgesia of ...[more]

PMID: 28582470

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Project description:BACKGROUND:The proinflammatory cytokine interleukin-1? (IL-1?) drives pain by inducing the expression of inflammatory mediators; however, its ability to regulate sodium channel 1.7 (Nav1.7), a key driver of temporomandibular joint (TMJ) hypernociception, remains unknown. IL-1? induces cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). We previously showed that PGE2 upregulated trigeminal ganglionic Nav1.7 expression. Satellite glial cells (SGCs) involve in inflammatory pain through glial cytokines. Therefore, we explored here in the trigeminal ganglion (TG) whether IL-1? upregulated Nav1.7 expression and whether the IL-1? located in the SGCs upregulated Nav1.7 expression in the neurons contributing to TMJ inflammatory hypernociception. METHODS:We treated rat TG explants with IL-1? with or without inhibitors, including NS398 for COX-2, PF-04418948 for EP2, and H89 and PKI-(6-22)-amide for protein kinase A (PKA), or with adenylate cyclase agonist forskolin, and used real-time PCR, Western blot, and immunohistofluorescence to determine the expressions or locations of Nav1.7, COX-2, cAMP response element-binding protein (CREB) phosphorylation, and IL-1?. We used chromatin immunoprecipitation to examine CREB binding to the Nav1.7 promoter. Finally, we microinjected IL-1? into the TGs or injected complete Freund's adjuvant into TMJs with or without previous microinjection of fluorocitrate, an inhibitor of SGCs activation, into the TGs, and evaluated nociception and gene expressions. Differences between groups were examined by one-way analysis of variance (ANOVA) or independent samples t test. RESULTS:IL-1? upregulated Nav1.7 mRNA and protein expressions in the TG explants, whereas NS398, PF-04418948, H89, or PKI-(6-22)-amide could all block this upregulation, and forskolin could also upregulate Nav1.7 mRNA and protein expressions. IL-1? enhanced CREB binding to the Nav1.7 promoter. Microinjection of IL-1? into the TGs or TMJ inflammation both induced hypernociception of TMJ region and correspondingly upregulated COX-2, phospho-CREB, and Nav1.7 expressions in the TGs. Moreover, microinjection of fluorocitrate into the TGs completely blocked TMJ inflammation-induced activation of SGCs and the upregulation of IL-1? and COX-2 in the SGCs, and phospho-CREB and Nav1.7 in the neurons and alleviated inflammation-induced TMJ hypernociception. CONCLUSIONS:Glial IL-1? upregulated neuronal Nav1.7 expression via the crosstalk between signaling pathways of the glial IL-1?/COX-2/PGE2 and the neuronal EP2/PKA/CREB/Nav1.7 in TG contributing to TMJ inflammatory hypernociception.

Project description:Pain is a common symptom associated with disorders involving the orofacial structures. Most acute orofacial painful conditions are easily recognized, but the pharmacological treatment may be limited by the adverse events of current available drugs and/or patients’ characteristics. In addition, chronic orofacial pain conditions represent clinical challenges both, in terms of diagnostic and treatment. There is growing evidence that specialized pro-resolution lipid mediators (SPMs) present potent analgesic effects, in addition to their well characterized role in the resolution of inflammation. Maresins (MaR-1 and MaR-2) were the last described members of this family, and MaR-2 analgesic action has not yet been reported. Herein the effect of MaR-2 in different orofacial pain models was investigated. MaR-2 (1 or 10 ng) was always delivered via medullary subarachnoid injection, which corresponds to the intrathecal treatment. A single injection of MaR-2 caused a significant reduction of phases I and II of the orofacial formalin test in rats. Repeated injections of MaR-2 prevented the development of facial heat and mechanical hyperalgesia in a model of post-operative pain in rats. In a model of trigeminal neuropathic pain (CCI-ION), repeated MaR-2 injections reversed facial heat and mechanical hyperalgesia in rats and mice. CCI-ION increased c-Fos positive neurons and CGRP+ activated (nuclear pNFkB) neurons in the trigeminal ganglion (TG), which were restored to sham levels by MaR-2 repeated treatment. In conclusion, MaR-2 showed potent and long-lasting analgesic effects in inflammatory and neuropathic pain of orofacial origin and the inhibition of CGRP-positive neurons in the TG may account for MaR-2 action. Graphical abstract Image 1 Highlights • MaR-2 reduces formalin-induced nociceptive behavior.• MaR-2 prevents heat and mechanical hyperalgesia in the postoperative pain model.• MaR-2 reverses heat and mechanical hyperalgesia in a neuropathic pain model.• MaR-2 reduces c-Fos activation in the trigeminal ganglion.• MaR-2 reduces the activation of CGRP+ neurons in the trigeminal ganglion.

Dataset Information

Estradiol upregulates voltage-gated sodium channel 1.7 in trigeminal ganglion contributing to hyperalgesia of inflamed TMJ.

Background

Methods

Results

Conclusion

Publications

Estradiol upregulates voltage-gated sodium channel 1.7 in trigeminal ganglion contributing to hyperalgesia of inflamed TMJ.

Similar Datasets

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