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触发器和结果 （TMJD）疼痛，造成恶性循环，可能加剧男性和女性的疼痛。为 原因尚不清楚，据报道，TMJD和压力在女性中更为普遍。临床前 研究表明，亚慢性到慢性压力会加剧男性和女性的疼痛。 受试者，然而，压力对闭合性TMJD疼痛及其潜在机制的作用是 不清楚在压力对人的影响方面，仍然有可能存在未被发现的性别差异。 三叉神经的神经生物学，这可能有助于TMJD疼痛的二态患病率。一 压力加剧TMJD疼痛的可能机制可能归因于双相性 三叉神经节（TG）感觉神经元传入的神经组织和/或功能 臂旁核（PBN）。另外，或者说，神经胶质细胞可能在性行为中发挥作用。 TMJD疼痛期间这些回路的二态调制。当PBN中的小胶质细胞被激活时 在压力和口面疼痛，并有助于炎症，小胶质细胞在压力中的作用， 男性和女性PBN中TMJD疼痛加重的情况仍然未知。一种两性异形 压力对TMJD疼痛的影响可能是TMJD在老年人中更普遍的一个因素。 女性和填补空白，我们的知识的神经生物学机制，在三叉神经 有助于疼痛的系统对于最终改善疼痛管理至关重要。我们的总体 假设PBN功能的性别差异有助于应激加剧疼痛行为 在闭塞性TMJD大鼠模型中。F31的目标将测试我们的工作假设， 两个具体目标：具体目标1将决定是否PBN神经元的神经活动接受 来自颞下颌关节的感觉输入有助于压力加剧疼痛行为的性别差异。 具体目标2将确定PBN小胶质细胞是否有助于压力的性别差异 加重了闭塞性TMJD大鼠模型的疼痛行为。根据这些设计的实验 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、多重蛋白质组分析仪阵列和基因测序来测试 PBN在应激状态下加重口面部疼痛。我们的初步数据有力地支持了 假设和我们的研究结果有可能填补知识的主要空白的有害 压力的影响是TMJD疼痛的重要触发因素和结果。

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.