Estrogen and Psychological Stress in TMJD Pain

描述（由申请方提供）：颞下颌关节/肌肉疾病（TMJD）代表了一系列存在颞下颌关节（TMJ）和咀嚼肌疼痛的疾病。慢性TMJD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TMJD患者显示出最小的组织损伤迹象，并且从常规抗炎药物治疗中获益很少。慢性TMJD的症状提示中枢神经功能障碍或疼痛放大的问题。相比之下，大多数TMJ伤害感受的动物模型依赖于明显的炎症并且不考虑已知的风险因素（即，雌激素状态和压力）。在本申请中，我们将使用一个已建立的心理应激模型，重复强迫游泳试验（FST），已知诱导持续性痛觉过敏，并将确定其对颞下颌关节伤害性处理雌性大鼠在高和低雌激素条件下的影响。我们将测试的假设，雌激素状态和心理压力的变化，通过周围的导水管灰质-吻侧延髓腹内侧（PAG-RVM），主要的脊髓上疼痛调节系统，影响颞下颌关节伤害性感受。由于多巴胺能（5 HT）机制介导了PAG对脊髓系统诱导作用的重要部分，我们将测试特定的5 HT受体是否参与背角水平TMJ伤害性处理的调节。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/上颈后角区域（Vc/C1-2）的单个神经元活动，这是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TMJ伤害性感受的外周行为相关性的影响。提出了三个具体目标。目的1将确定雌激素状态是否改变PAG诱导的调制TMJ诱发的单位活动，咬肌肌电图和c-fos免疫反应神经元在Vc/C1-2区在假手术和FST条件大鼠。目的2将确定尾侧脑干水平的5-HT受体的局部作用是否有助于PAG诱导的TMJ伤害性感受的调制。目的3将确定5 HT受体在尾侧脑干水平的局部作用是否独立于明显的PAG刺激而改变对TMJ刺激的反应。这些研究将为雌激素状态和心理压力对脑干系统神经生物学的影响提供新的信息，脑干系统被认为是TMJD疼痛的关键。公共卫生相关性：下颌关节和咀嚼肌疼痛是持续性面部疼痛的最常见形式。女性以及抑郁症和心理压力的共同发生是公认的发生持续性颌骨疼痛的危险因素。通过使用考虑这些已知风险因素的新动物模型，我们对持续性颌骨疼痛的神经生物学的理解将得到改善。

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.