Female Pelvic Pain, Hormones, and Neuroplasticity

女性盆腔疼痛、激素和神经可塑性

• 批准号: 7225475
• 负责人: Peter G Smith
• 金额: $ 26.66万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-16 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225475
• 关键词: Adolescent; Adult; Animal Model; Atrophic; Autonomic ganglion; Axon; Behavior; Behavioral; Biological; Biopsy; Blood flow; Burn injury; Burning Pain; Calcitonin Gene-Related Peptide; Caliber; Cellular biology; Condition; Contraceptive Usage; Culture Media; Disease; Down-Regulation; Dryness; Estrogen Receptors; Estrogens; Estrous Cycle; Estrus; Etiology; Female; Fiber; Functional disorder; Gene Expression; Gene Proteins; Genital system; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Human; Immunoblotting; In Vitro; Intervention; Juvenile Hormones; Lead; Link; Mediating; Menopausal Syndrome; Menopause; Methods; Microarray Analysis; Molecular; Molecular Biology; Nerve; Neurites; Neurogenic Inflammation; Neuronal Plasticity; Neurons; Neuropeptides; Nociceptors; Numbers; Operative Surgical Procedures; Oral; Oral Contraceptives; Ovariectomy; Pain; Pelvic Pain; Peripheral Nerves; Pharmacology; Physiology; Population; Pregnancy; Proteins; Pruritus; Rattus; Response Latencies; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory; Stimulus; Syndrome; Testing; Tissues; Touch sensation; Vagina; Vascular Permeabilities; Vulva; Vulvodynia; allodynia; awake; behavior test; density; insight; nerve supply; neuromechanism; neuronal cell body; novel therapeutics; protein expression; release factor; reproductive; reproductive hormone; research study; tissue culture

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.

描述（由申请人提供）：荷尔蒙状态和阴道功能紧密相关。更年期的生殖激素减少导致阴道萎缩和干燥。更年期通常伴有发抖性外阴痛，这是一种疼痛综合征，包括燃烧和瘙痒。连同外阴前庭炎，一种与早期口服避孕药相关的类肌综合症，外阴痛代表了一个不认可但重大的健康问题，遭受了约16％的美国成年女性人群。这些综合征的病因尚不清楚，尽管外阴前庭炎与疼痛感应纤维数量增加有关。没有动物模型可提供更好的理解框架。最近，我们表明雌激素调节大鼠的阴道神经支配。卵巢切除术，近似于人类的更年期，大大增加了阴道感官伤害感受器的数量，以及交感神经和副交感神经轴突。我们假设这是由于对阴道组织的营养因子释放的调节，并且神经支配的改变将影响阴道功能的关键方面，包括血液流动，血管渗透性和疼痛敏感性。在AIM 1中，我们建议表征在发情周期，妊娠以及成人和青少年激素给药期间大鼠激素状态与阴道神经支配之间的关系。我们还确定人的阴道神经是否随激素状态变化。 AIM 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，评估轴突重塑的基础机制。 AIM 3检查了通过研究潜在营养因子的表达和功能相关性来介导阴道重塑的分子机制。在AIM 4中，我们评估了阴道神经重塑对血流，神经源性炎症和避免疼痛刺激行为的功能意义。这些研究是使用细胞生物学，组织培养，分子生物学，生理学，药理学和行为的方法进行的。这些实验的发现将提供对阴道神经支配激素依赖性重塑的机制的见解，以及神经支配是否改变可能导致阴道功能障碍。此外，这些研究将更好地理解阴道神经可塑性和外阴痛之间的关系，并有可能导致旨在逆转阴道感觉过度感染的新治疗剂。