Female Pelvic Pain, Hormones, and Neuroplasticity

描述(申请人提供)：荷尔蒙状况和阴道功能密切相关。更年期生殖激素减少会导致阴道萎缩和干燥。更年期通常伴随着外阴功能障碍，这是一种由灼热和瘙痒组成的疼痛综合征。外阴前庭炎是一种与早期使用口服避孕药有关的类似超感痛症的综合征，与外阴前庭炎一起，外阴疼痛是一个未得到充分认识但意义重大的健康问题，困扰着大约16%的美国成年女性人口。尽管外阴前庭炎与疼痛感受性纤维的数量增加有关，但这些综合征的病因尚不清楚。目前还没有动物模型可以提供更好的理解框架。最近，我们发现雌激素对大鼠的阴道神经支配有调节作用。卵巢切除术接近人类更年期，极大地增加了阴道感受器以及交感和副交感轴突的数量。我们假设这是由于调节了阴道组织中营养因子的释放，神经支配的改变将影响阴道功能的关键方面，包括血流、血管通透性和疼痛敏感性。在目标1中，我们建议描述大鼠发情周期、妊娠以及成年和幼年激素使用期间荷尔蒙状态与阴道神经支配的关系。我们还确定人类的阴道神经是否会随着荷尔蒙状态的变化而变化。目的2通过测定生殖激素对阴道靶组织以及感觉和自主神经的影响，评估轴突重塑的细胞机制。目的3通过研究潜在营养因子的表达和功能相关性，探讨介导阴道重塑的分子机制。在目标4中，我们评估了阴道神经重塑对血流、神经源性炎症和对疼痛刺激的行为回避的功能意义。这些研究使用了细胞生物学、组织培养、分子生物学、生理学、药理学和行为学的方法。这些实验的发现将提供对阴道神经激素依赖性重塑的潜在机制的洞察，以及神经改变是否可能导致阴道功能障碍。此外，这些研究将更好地了解阴道神经可塑性与外阴疼痛之间的关系，并可能导致旨在逆转阴道感觉过度神经支配的新疗法。

DESCRIPTION (provided by applicant): Hormonal status and vaginal function are closely linked. Diminished reproductive hormones at menopause lead to vaginal atrophy and dryness. Menopause is often accompanied by dysesthetic vulvodynia, a pain syndrome consisting of burning and itching. Together with vulvar vestibulitis, an allodynia-like syndrome linked to early oral contraceptive use, vulvodynia represents an under-recognized but significant health problem, afflicting some 16% of the adult US female population. The etiology of these syndromes is poorly understood, although vulvar vestibulitis is associated with increased numbers of pain-sensing fibers. No animal models have been available to provide a better framework of understanding. Recently, we showed that estrogen regulates vaginal innervation in rats. Ovariectomy, which approximates human menopause, dramatically increases numbers of vaginal sensory nociceptors, as well as sympathetic and parasympathetic axons. We hypothesize that this is due to modulation of trophic factor release from vaginal tissues, and that altered innervation will influence key aspects of vaginal function, including blood flow, vascular permeability, and pain sensitivity. In aim 1 we propose to characterize the relationship between hormonal status and vaginal innervation in rats during the estrous cycle, pregnancy, and adult and juvenile hormone administration. We also determine if human vaginal innervation varies with hormonal state. Aim 2 assesses cellular mechanisms underlying axonal remodeling by determining effects of reproductive hormones on vaginal target tissue and on sensory and autonomic neurons. Aim 3 examines molecular mechanisms mediating vaginal remodeling by investigating expression and functional relevance of potential trophic factors. In aim 4, we assess the functional significance of vaginal nerve remodeling on blood flow, neurogenic inflammation and behavioral avoidance of painful stimuli. These studies are conducted using methods in cell biology, tissue culture, molecular biology, physiology, pharmacology and behavior. The findings of these experiments will provide insight into mechanisms underlying hormone-dependent remodeling of vaginal innervation, and whether altered innervation may contribute to vaginal dysfunction. Moreover, these studies will provide a better understanding of the relationship between vaginal nerve plasticity and vulvodynia, and potentially lead to new therapeutics aimed at reversing vaginal sensory hyperinnervation.