Female Pelvic Pain, Hormones,and Neuroplasticity

描述（由申请人提供）：激素状态与阴道功能密切相关。绝经期生殖激素的减少会导致阴道萎缩和干燥。更年期常伴有外阴痛觉，这是一种由灼烧和瘙痒组成的疼痛综合征。外阴痛与外阴前庭炎（一种与早期使用口服避孕药有关的异位性疼痛样综合征）一起，是一种未被充分认识但重要的健康问题，困扰着约16%的美国成年女性人口。这些综合征的病因尚不清楚，尽管外阴前庭炎与痛觉纤维数量增加有关。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，显着增加阴道感觉伤害感受器的数量，以及交感和副交感轴突。我们假设这是由于阴道组织中营养因子释放的调节，而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。在目的1中，我们建议描述大鼠在发情周期、怀孕以及成年和幼年激素给药期间激素状态和阴道神经支配之间的关系。我们还确定了人类阴道神经支配是否随激素状态而变化。目的2通过确定生殖激素对阴道靶组织以及感觉和自主神经元的影响来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来研究介导阴道重塑的分子机制。在目的4中，我们评估了阴道神经重塑对血流、神经源性炎症和疼痛刺激行为回避的功能意义。这些研究使用细胞生物学、组织培养、分子生物学、生理学、药理学和行为学等方法进行。这些实验的发现将深入了解阴道神经支配激素依赖性重塑的机制，以及神经支配的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痛之间的关系，并有可能导致旨在逆转阴道感觉神经亢进的新疗法。

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.