Estrogen and Psychological Stress in TMJD Pain

描述(申请人提供)：颞下颌关节/肌肉紊乱病(TMJD)是一组以颞下颌关节(TMJ)和咀嚼肌疼痛为表现的疾病。慢性TMJD主要发生在年轻女性，并与高水平的心理压力密切相关。慢性TMJD患者表现出轻微的组织损伤迹象，并且几乎不能从传统的抗炎药物治疗中受益。慢性TMJD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伤害性动物模型依赖于明显的炎症，没有考虑已知的危险因素(即雌激素状态和压力)。在这项应用中，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)，已知可诱导持续性痛敏，并将确定其在高和低雌激素条件下对雌性大鼠TMJ伤害性加工的影响。我们将验证这一假设，即雌激素状态和心理应激的变化通过导水管周围灰质-吻部延髓腹内侧区(PAG-RVM)影响TMJ伤害性感受。由于5-羟色胺(5-羟色胺，5-羟色胺)能机制介导了PAG对脊髓系统产生的很大一部分效应，我们将测试特定的5-羟色胺受体是否参与了TMJ在背角水平的伤害性处理的调制。我们将通过注射非炎症性物质三磷酸腺苷来刺激TMJ传入纤维，并记录三叉神经尾侧亚核/上颈背角区域(VC/C1-2)的单个神经元活动，这是TMJ伤害性感受器的主要终末部位。咬肌肌电(EMG)活动将使我们能够评估对与TMJ伤害性感觉相关的外周行为的治疗效果。提出了三个具体目标。目的1确定雌激素状态是否改变PAG对假手术和FST大鼠TMJ诱发单位活动、咬肌肌电和c-fos免疫反应神经元的调节。目的2将确定5-羟色胺受体在尾侧脑干水平的局部作用是否参与PAG诱导的TMJ伤害性感受的调制。目的3将确定5-羟色胺受体单独在尾侧脑干水平的局部作用是否改变对TMJ刺激的反应而不依赖于PAG的显性刺激。这些研究将为雌激素状态和心理应激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：下颌关节和咀嚼肌肉疼痛是最常见的持续性面部疼痛形式。女性和与抑郁疾病和心理压力并存是公认的发生持续性下巴疼痛的危险因素。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.