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，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，这些条件是3- 4倍 在女性中普遍存在。女性更容易经历与颞下颌关节相关的剧烈疼痛 这些患者更容易出现疼痛障碍，也更可能经历疼痛合并症和广泛疼痛。虽然很明显 颅面疼痛是男性和女性的主要健康问题，女性在疼痛中没有很好的代表性。 research.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 调节颅面疼痛然而，在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。我们已经描述了一种新的疼痛机制， 主要的雌激素17 β-雌二醇（E2），作用于位于伤害感受器的核雌激素受体α（ER α）， 三叉神经感觉神经元，放大口面疼痛信号。具体地说，E2加剧了前伤害感受性， 单胺神经递质5-羟色胺（5-HT）对伤害性三叉神经感觉神经元的作用。而 众所周知，5-HT在中枢神经系统中在情绪和抗伤害感受中的作用，其在中枢神经系统中的矛盾作用， 外周通过感觉神经元促进疼痛信号传导。我们已经报道过， 5-HT对三叉神经感觉神经元的作用受E2的调节， 在三叉神经感觉神经元的环境中尚未被定义。5 HT通过5 HT被主动摄取 转运机制和释放的血小板，肥大细胞，受损的上皮细胞，和各种免疫 细胞，如巨噬细胞。在临床前和临床试验中，5-HT水平升高与高E2相关。 临床研究，我们有初步的数据表明，E2可以改变释放的5 HT，和其他 炎症介质，从巨噬细胞。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三叉神经感觉神经元的多巴胺能神经免疫调节 颞下颌关节紊乱疼痛。我们的研究旨在确定17β-雌二醇（通过 ERα、ERβ和/或G蛋白雌激素受体GPER）对肾上腺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的联系。我们将使用一个 单侧前牙反牙合（UAC）的平移动物模型，我们有初步的数据表征 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， 在口面神经感觉研究方面培训本科生和研究生。

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.