Sex Differences in the Neuroimmune Modulation of Trigeminal Sensory Neurons

摘要 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、 以及与颞下颌关节紊乱相关的疼痛。令人费解的是，这些条件多了 3-4 倍 多见于女性。女性更容易经历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。虽然很明显 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 研究。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 雌激素作用的神经元仍然难以捉摸。我们描述了一种新的疼痛机制，通过该机制 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，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。同时 5HT 以其在情绪和中枢神经系统抗伤害方面的作用而闻名，但它在 外周负责通过感觉神经元发出疼痛信号。我们已经报道过，亲伤害性 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 三叉神经感觉神经元的环境尚未确定。 5HT通过5HT主动吸收 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 细胞，例如巨噬细胞。在临床前和临床试验中，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 炎症介质，来自巨噬细胞。本提案中概述的实验将检验以下假设： 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 颞下颌关节紊乱疼痛。我们的研究旨在确定 17β-雌二醇的作用（通过 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 三叉神经节神经元和三叉神经节巨噬细胞之间。我们将使用以下方法检验我们的假设 我们拥有初步表征的单侧前牙反合 (UAC) 转化动物模型 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 培训口面部神经感觉研究的本科生和研究生。

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.