Sex Differences in Stress Exacerbated Orofacial Pain in a Rat Model of Temporomandibular Joint Disorder

摘要 据报道，心理压力是颞下颌关节紊乱病的诱因和结果。 (TMJD)疼痛，造成恶性循环，会加剧男性和女性的疼痛。为 原因不明，据报道，TMJD和压力在女性中更普遍。临床前 研究表明，亚慢性或慢性压力会加剧男性和女性的疼痛 受试者，然而，压力对闭塞性TMJD疼痛的作用及其潜在机制是 不清楚。仍然有可能在压力的影响上存在未被发现的性别差异 三叉神经生物学可能在TMJD疼痛的二相性流行中起作用。一 应激加重TMJD疼痛的可能机制可能归因于二相性 三叉神经节感觉神经元传入的神经组织和/或功能 臂旁核(PBN)此外，或者作为替代，神经胶质细胞可能在性行为中发挥作用 在TMJD疼痛过程中，这些回路的二态调制。当PBN中的小胶质细胞被激活时 在应激和口腔面部疼痛和炎症过程中，小胶质细胞在应激中的作用 男性和女性PBN中加重的TMJD疼痛仍不清楚。性双形者 压力对TMJD疼痛的影响可能是TMJD在中国患病率较高的原因之一 女性和填补我们对三叉神经神经生物学机制知识的空白 促进疼痛的系统是最终改善疼痛管理的关键。我们最重要的是 假设PBN功能的性别差异导致应激加剧的疼痛行为 在闭塞性TMJD大鼠模型中。这款F31的目标将测试我们的工作假设 两个特定目标：特定目标1将决定PBN神经元的神经活动是否 来自TMJ的感觉输入导致了应激加剧疼痛行为的性别差异。 特定目标2将确定PBN小胶质细胞是否对应激中的性别差异起作用 加重闭塞性TMJD大鼠的疼痛行为。在此基础上设计的实验 AIMS将利用行为分析、免疫组织化学、共聚焦显微镜、 流式细胞术、多重蛋白质组谱分析阵列和基因测序以测试 应激状态下的PBN加重了口面部疼痛。我们的初步数据为 假说和我们的结果有可能填补关于有害物质的主要知识空白 应激作为TMJD疼痛的重要触发和结果的影响。

Abstract Psychological stress is reported to be a trigger and a result of temporomandibular joint disorder (TMJD) pain, creating a vicious cycle that can exacerbate pain in both men and women. For reasons unclear, TMJD and stress are reported to be more prevalent in women. Preclinical research indicates that subchronic to chronic stress can exacerbate pain in male and female subjects, however the role of stress on occlusive TMJD pain and its underlying mechanisms is unclear. It remains possible that there are undetected sex differences in the effects of stress on trigeminal neurobiology which may contribute to the dimorphic prevalence of TMJD pain. One possible mechanism underlying stress exacerbated TMJD pain may be attributed to dimorphic neural organization and/or function of the trigeminal ganglia (TG) sensory neuron afferents to the parabrachial nucleus (PBN). Additionally, or alternatively, glial cells may play a role in the sexually dimorphic modulation of these circuits during TMJD pain. As microglia in the PBN are activated during both stress and orofacial pain and contribute to inflammation, the role of microglia in stress exacerbated TMJD pain in the PBN of males and females remains unknown. A sexually dimorphic effect of stress on TMJD pain may be one factor underlying the greater prevalence of TMJD in women and filling gaps in our knowledge of the neurobiological mechanisms in the trigeminal system contributing to pain is critical to ultimately improving pain management. Our overarching hypothesis is that sex differences in PBN function contribute to stress exacerbated pain behaviors in a rat model of occlusive TMJD. The goals for this F31 will test our working hypothesis across two specific aims: Specific Aim 1 will determine whether neural activity of PBN neurons receiving sensory input from the TMJ contribute to sex differences in stress exacerbated pain behaviors. Specific Aim 2 will determine whether PBN microglia contribute to sex differences in stress exacerbated pain behaviors in a rat model of occlusive TMJD. Experiments designed under these aims will utilize a combination of behavioral assays, immunohistochemistry, confocal microscopy, flow cytometry, multiplex proteome profiler arrays, and gene sequencing to test the role of the PBN in stress exacerbated orofacial pain. Our preliminary data provide strong support for the hypothesis and our results have the potential to fill a major gap in knowledge on the deleterious effects of stress as a significant trigger and result of TMJD pain.