Estrogen and Psychological Stress in TMJD Pain

描述（由申请人提供）：颞下颌关节/肌肉疾病（TMJD）代表了以颞下颌关节（TMJ）和咀嚼肌肉疼痛为表现的一系列疾病。慢性颞下颌关节痛主要发生在年轻女性中，与心理压力水平升高密切相关。慢性颞下颌关节痛患者表现出最小的组织损伤迹象，从传统的抗炎药物治疗中获益甚微。慢性颞下颌关节痛的症状提示中枢神经功能障碍或疼痛放大问题。相比之下，大多数TMJ伤害感觉的动物模型依赖于明显的炎症，而不考虑已知的危险因素（即雌激素状态和应激）。在这个应用中，我们将使用一个已建立的心理应激模型，即重复强迫游泳试验（FST），已知会诱发持续性痛觉过敏，并将确定其对雌性大鼠在高雌激素和低雌激素条件下TMJ伤害性加工的影响。我们将检验雌激素水平的变化和心理应激通过导管周围灰吻侧腹内侧髓质（PAG-RVM）这一主要的脊柱上疼痛调节系统影响颞下颌关节伤害感受的假设。由于5 -羟色胺能（5HT）机制介导了PAG诱导的脊髓系统效应的重要部分，我们将测试特定的5HT受体是否参与颞下颌关节背角水平伤害性加工的调节。我们将通过注射非炎症剂ATP刺激TMJ传入纤维，并记录三叉神经尾侧亚核/上颈背角区（Vc/C1-2）的单个神经元活动，该区域是TMJ伤害感受器的主要终止部位。咬肌肌电图（EMG）活动将使我们能够评估治疗对颞下颌关节伤害感觉的外周行为相关的影响。提出了三个具体目标。目的1将确定雌激素状态是否会改变假手术和fst条件大鼠中pag诱导的tmj诱发的单位活性、咬肌肌电图和Vc/C1-2区c-fos免疫反应神经元的调节。目的2将确定5HT受体在尾侧脑干水平的局部作用是否有助于pag诱导的TMJ伤害感觉的调节。目的3将确定5HT受体在尾侧脑干水平的局部作用是否独立于明显的PAG刺激改变颞下颌关节刺激的反应。这些研究将为雌激素水平和心理应激对脑干系统神经生物学的影响提供新的信息，这些系统被认为是颞下颌关节痛的关键。公共卫生相关性：下颌关节和咀嚼肌肉疼痛是持续性面部疼痛最常见的形式。女性以及抑郁症和心理压力的共同发生是发生持续性下颌疼痛的公认危险因素。我们对持续下颌疼痛的神经生物学的理解将通过使用考虑这些已知危险因素的新动物模型得到改善。

Description (provided by applicant): Temporomandibular joint/muscle disorders (TMJD) represent a family of conditions that present with pain in the temporomandibular joint (TMJ) and muscles of mastication. Chronic TMJD occurs mainly in young women and is strongly associated with elevated levels of psychological stress. Chronic TMJD patients display minimal signs of tissue injury and benefit little from conventional anti-inflammatory drug therapies. The symptoms of chronic TMJD suggest a central neural dysfunction or problem of pain amplification. By contrast, most animal models of TMJ nociception rely on overt inflammation and do not account for known risk factors (i.e., estrogen status and stress). In this application we will use an established model of psychological stress, the repeated forced swim test (FST), known to induce persistent hyperalgesia and will determine its effects on TMJ nociceptive processing in female rats under high and low estrogen conditions. We will test the hypothesis that changes in estrogen status and psychological stress act through the periaqueductal gray-rostral ventromedial medulla (PAG-RVM), the main supraspinal pain modulatory system, to influence TMJ nociception. Since serotonergic (5HT) mechanisms mediate a significant portion of PAG- induced effects on spinal systems, we will test if specific 5HT receptors are involved in modulation of TMJ nociceptive processing at the dorsal horn level. We will stimulate TMJ afferent fibers by injection of the non-inflammatory agent, ATP, and record single neuron activity at the trigeminal subnucleus caudalis/upper cervical dorsal horn region (Vc/C1-2), the principal site of termination for TMJ nociceptors. Masseter muscle electromyographic (EMG) activity will allow us to assess treatment effects on a peripheral behavioral correlate of TMJ nociception. Three Specific Aims are proposed. Aim 1 will determine if estrogen status alters PAG-induced modulation of TMJ-evoked unit activity, masseter muscle EMG and c-fos immunoreactive neurons at the Vc/C1-2 region in sham and FST-conditioned rats. Aim 2 will determine if local actions of 5HT receptors at the caudal brainstem level contribute to PAG-induced modulation of TMJ nociception. Aim 3 will determine if local actions of 5HT receptors alone at the caudal brainstem level modify the responses to TMJ stimulation independent of overt PAG stimulation. These studies will provide new information on the influence of estrogen status and psychological stress on the neurobiology of brainstem systems thought to be critical for TMJD pain. PUBLIC HEALTH RELEVANCE: Pain in the jaw joint and muscles of mastication is the most common form of persistent facial pain. Female gender and co-occurrence with depressive illness and psychological stress are recognized risk factors in developing persistent jaw pain. Our understanding of the neurobiology of persistent jaw pain will be improved by the use of new animal models that consider these known risk factors.