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.

抽象的大约四分之一的人口经历口腔和颅面疼痛，例如头痛、偏头痛、与颞下颌关节紊乱相关的疼痛令人费解的是，这些病症的数量增加了 3-4 倍。女性更容易出现与颞下颌关节相关的剧烈疼痛。疾病，也更有可能出现疼痛合并症和广泛的疼痛。颅面疼痛对于男性和女性来说都是一个主要的健康问题，但女性在疼痛中的比例并不高在包括检查女性受试者的临床和临床前研究中，雌激素显然可以。调节颅面疼痛然而，三叉神经感觉的潜在颅面疼痛机制。我们已经描述了一种新的疼痛机制，雌激素所作用的神经元仍然难以捉摸。主要雌激素 17-雌二醇 (E2)，作用于定位于伤害性的核雌激素受体 α (ER) 三叉神经感觉神经元会放大口面部疼痛信号，具体来说，E2 会加剧伤害感受。单胺神经递质血清素（5HT）对伤害性三叉神经感觉神经元的影响。 5HT 因其在中枢神经系统中的情绪和预感方面的作用而闻名，但它在我们已经报道过，外周神经元通过感觉神经元促进疼痛信号传导。 5HT对三叉神经感觉神经元的作用受E2调节，然而5HT与E2之间的关系在三叉神经感觉神经元的环境中，5HT 是通过 5HT 主动吸收的。转运机制并由血小板、肥大细胞、受损上皮细胞和各种免疫细胞释放在临床前和临床前研究中，巨噬细胞等细胞的 5HT 水平升高与高 E2 相关。临床研究，我们有初步数据表明 E2 可以改变 5HT 的释放，以及其他本提案中概述的实验将检验以下假设：来自巨噬细胞的炎症介质。雌激素增强大鼠模型中三叉神经感觉神经元的血清素能神经免疫调节我们的研究旨在确定 17β-雌二醇（通过）的作用。 ERα、ERβ 和/或 G 蛋白雌激素受体 GPER）对血清素能神经免疫通讯的影响我们将使用三叉神经节神经元和三叉神经节巨噬细胞之间的关系来检验我们的假设。我们拥有初步表征的单侧前牙反合 (UAC) 转化动物模型该项目还将提供一个具有挑战性的实验框架。培训口面部神经感觉研究的本科生和研究生。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Estrogen modulation of the pronociceptive effects of serotonin on female rat trigeminal sensory neurons is timing dependent and dosage dependent and requires estrogen receptor alpha.

雌激素对雌性大鼠三叉神经感觉神经元血清素的促伤害作用的调节具有时间依赖性和剂量依赖性，并且需要雌激素受体α。

DOI：
发表时间：
2022-08-01
期刊：
影响因子：
7.4
作者：
Kaur, Sukhbir;Hickman, Taylor M;Lopez;McDonald, Hanna;Lockhart, Lauren M;Darwish, Omar;Averitt, Dayna Loyd
通讯作者：
Averitt, Dayna Loyd

Progesterone and Allopregnanolone Rapidly Attenuate Estrogen-Associated Mechanical Allodynia in Rats with Persistent Temporomandibular Joint Inflammation.

黄体酮和异孕酮可快速减轻持续性颞下颌关节炎症大鼠中雌激素相关的机械异常性疼痛。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Hornung, Rebecca S;Benton, William L;Tongkhuya, Sirima;Uphouse, Lynda;Kramer, Phillip R;Averitt, Dayna Loyd
通讯作者：
Averitt, Dayna Loyd

Sigma-1 receptors and progesterone metabolizing enzymes in nociceptive sensory neurons of the female rat trigeminal ganglia: A neural substrate for the antinociceptive actions of progesterone.

雌性大鼠三叉神经节伤害性感觉神经元中的 Sigma-1 受体和孕酮代谢酶：孕酮抗伤害作用的神经底物。

DOI：
发表时间：
2022
期刊：
影响因子：
3.3
作者：
Hornung, Rebecca S;Raut, Namrata Gr;Cantu, Daisy J;Lockhart, Lauren M;Averitt, Dayna L
通讯作者：
Averitt, Dayna L

Estrogen exacerbates the nociceptive effects of peripheral serotonin on rat trigeminal sensory neurons.

雌激素加剧外周血清素对大鼠三叉神经感觉神经元的伤害作用。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Kaur, Sukhbir;McDonald, Hanna;Tongkhuya, Sirima;Lopez, Cierra M C;Ananth, Sushmitha;Hickman, Taylor M;Averitt, Dayna L
通讯作者：
Averitt, Dayna L