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Sex Differences in the Neuroimmune Modulation of Trigeminal Sensory Neurons

三叉神经感觉神经元神经免疫调节的性别差异

基本信息

批准号：
10730658
负责人：
Dayna Loyd Averitt
金额：
$ 38.34万
依托单位：
TEXAS WOMAN'S UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730658
关键词：
Academy Address Afferent Neurons Age American Animal Model Anterior Arthralgia Binding Biomedical Research Blood Platelets Cell Culture Techniques Cells Central Nervous System Clinical Research Communication Complex Contraceptive Usage Craniofacial Pain Cross Bite Data Development Dichloromethylene Diphosphonate Environment Epithelial Cells Estradiol Estrogen Nuclear Receptor Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Female Funding GPER gene GTP-Binding Proteins Genes Grant Headache Health Hyperalgesia Immune Inflammation Mediators Inflammatory Injury Knowledge Liposomes Luteal Phase Macrophage Mediating Medicine Menarche Menstruation Methods Migraine Modeling Moods Myeloid Cells Neuroanatomy Neuroimmune Neurons Neurotransmitters Nociception Nociceptors Oral Contraceptives Orofacial Pain Ovarian hormone Pain Pain Research Patients Peripheral Pharmacology Population Postmenopause Prevalence Probability Progesterone Rattus Recommendation Reporting Research Rodent Role Serotonergic System Serotonin Sex Differences Signal Transduction Site Source Stress Structure of trigeminal ganglion TRPV1 gene Temporomandibular Joint Temporomandibular Joint Disorders Temporomandibular joint disorder pain Testing Texas Therapeutic Training Trigeminal Pain Trigeminal System Universities Woman antinociception behavior test chemokine chronic pain chronic painful condition comorbidity craniofacial cytokine design differential expression estrophilin experience experimental study graduate student immune cell infiltrate insight male mast cell men monoamine monocyte neurosensory novel oral pain orofacial pain behavior pain signal preclinical study receptor reproductive sensory system serotonin transporter sex sexual dimorphism transcriptome transcriptomic profiling undergraduate student

项目摘要

Abstract Approximately a quarter of the population experiences oral and craniofacial pain, such as headache, migraine, and pain associated with temporomandibular joint disorders. Inexplicably, these conditions are 3-4x more prevalent in women. Women are more likely to experience severe pain associated with temporomandibular joint disorders and are also more likely to experience pain comorbidities and widespread pain. While it is clear that craniofacial pain is a major health issue for both men and women, women are not well represented in pain research. In clinical and preclinical studies that include examining female subjects, it is evident that estrogen can modulate craniofacial pain. However, the underlying craniofacial pain mechanisms at the trigeminal sensory neurons by which estrogen acts on remain elusive. We have described a novel pain mechanism by which the major estrogen 17-estradiol (E2), acting on nuclear estrogen receptor alpha (ER) localized to nociceptive trigeminal sensory neurons, amplifies orofacial pain signaling. Specifically, E2 exacerbates the pronociceptive effects of the monoamine neurotransmitter serotonin (5HT) at nociceptive trigeminal sensory neurons. While 5HT is well-known for its role in mood and antinociception in the central nervous system, its paradoxical role in the periphery is to contribute to pain signaling by sensory neurons. We have reported that the pronociceptive effects of 5HT at trigeminal sensory neurons is modulated by E2, however the relationship between 5HT and E2 in the environment of trigeminal sensory neurons has not been defined. 5HT is actively taken up via 5HT transporter mechanisms and released by platelets, mast cells, damaged epithelial cells, and various immune cells, such as macrophages. Increased 5HT levels have been associated with high E2 in both preclinical and clinical studies and we have preliminary data indicating that E2 can alter the release of 5HT, and other inflammatory mediators, from macrophages. Experiments outlined in this proposal will test the hypothesis that estrogen enhances serotonergic neuroimmune modulation of trigeminal sensory neurons in a rat model of temporomandibular joint disorder pain. Our studies are designed to determine the effects of 17β-estradiol (via ERα, ERβ, and/or the G protein estrogen receptor GPER) on serotonergic neuroimmune communication between trigeminal ganglia neurons and trigeminal ganglia macrophages. We will test our hypothesis using a translational animal model of unilateral anterior crossbite (UAC) that we have preliminary data on characterizing the development of pain behaviors. This project will also provide a challenging experimental framework for training undergraduate and graduate students in orofacial neurosensory research.

摘要大约四分之一的人经历过口腔和颅面疼痛，如头痛、偏头痛、以及与颞下颌关节紊乱相关的疼痛。令人费解的是，这些情况要多出3-4倍多见于女性。女性更有可能经历与颞颌关节相关的剧烈疼痛而且更有可能经历疼痛、合并症和广泛性疼痛。虽然很明显，头面部疼痛是男性和女性的主要健康问题，女性在疼痛中没有得到很好的体现研究。在包括检查女性受试者的临床和临床前研究中，很明显雌激素可以调节头面部疼痛。然而，三叉神经感觉的潜在头面部疼痛机制雌激素作用于神经元的机制仍然难以捉摸。我们描述了一种新的疼痛机制，通过这种机制，主要雌激素17-雌二醇(E_2)作用于核雌激素受体α(ER-)，定位于伤害性感受三叉神经感觉神经元，放大口面部疼痛信号。具体地说，雌二醇加剧了前伤害感受性单胺类神经递质5-羟色胺对三叉神经伤害性感觉神经元的影响而当 5-羟色胺因其在中枢神经系统中对情绪和抗伤害感受的作用而广为人知，它在外周的作用是通过感觉神经元传递疼痛信号。我们已经报道了前伤害性感受器 5-羟色胺对三叉神经感觉神经元的作用受雌二醇的调节，但5-羟色胺与雌二醇的关系在三叉神经环境中的感觉神经元还没有定义。5羟色胺通过5羟色胺被积极接受转运机制和释放由血小板、肥大细胞、受损的上皮细胞和各种免疫细胞，如巨噬细胞。在临床前和临床前，5-羟色胺水平升高与高雌二醇水平有关临床研究和我们的初步数据表明，雌二醇可以改变5-羟色胺的释放，以及其他炎症介质，来自巨噬细胞。这项提案中概述的实验将检验这一假设雌激素增强大鼠三叉神经感觉神经元5-羟色胺能神经免疫调节颞下颌关节紊乱痛。我们的研究旨在确定17β-雌二醇(VIA)的作用 ERα、ERβ和/或G蛋白雌激素受体对5-羟色胺能神经免疫通讯的影响三叉神经节神经元和三叉神经节巨噬细胞之间。我们将使用一个单侧前牙反牙合动物模型的初步研究疼痛行为的发展。该项目还将提供一个具有挑战性的实验框架培训本科生和研究生进行口面部神经感觉研究。