AFFERENT PLASTICITY UNDERLYING URETHRAL AND PELVIC PAIN

以尿频、尿急和膀胱疼痛为特征的间质性膀胱炎(IC)等痛性膀胱综合征的患者通常表现为尿路或盆腔疼痛。骨盆周围神经损伤也可能导致膀胱和/或盆腔疼痛的出现，因为手术操作内脏器官是IC的危险因素，也经常导致盆腔疼痛患者现有症状的加重或新症状的出现。尿路、尿道括约肌和盆底由内脏(盆腔和腹下)和躯体(阴部)传入纤维的子集支配，这些传入纤维(C、Asigma和Abeta纤维；可能是Apha纤维)比支配膀胱的纤维(C和Asigma纤维)更多样化。然而，对于它们的功能特征和在慢性病理条件下的变化，包括组织炎症或神经损伤，可能导致慢性尿路或盆腔疼痛，人们知之甚少。因此，本研究将利用电生理学、药理学、分子和神经化学技术，对阴部神经中的尿路传入神经元和躯体传入神经元的特性进行研究。我们特别感兴趣的是这些传入神经元的膜特性，以及确定化学介质或病理如何改变离子通道和受体的特性，导致神经元的超兴奋性。将检验几个假设：(1)根据传入神经元的功能和形态特征，可以识别出多个亚型的传入神经元，包括河豚毒素抗性的Na+通道，慢速失活的瞬时K+通道，对辣椒素敏感的香草素受体(VR1)，以及对特定细胞标记物如神经丝或异凝素-B4的免疫反应；(2)慢性尿路/盆底炎症或直接损伤阴部神经改变了传入神经元中离子通道或神经递质机制的表达，导致这些神经元的过度兴奋。这些变化可能与我们最近在膀胱传入神经元上发现的不同。(3)慢性病理条件下，尿道传入神经元或阴部传入神经元的功能改变可通过重组内脏反射活动而引起膀胱和/或尿路活动亢进。该研究计划的长期目标是了解骨盆器官中刺激性或神经损伤刺激导致其传入路径的表型变化从而引发骨盆慢性疼痛的机制。如果发现不同的病理与离子通道或受体特性/表达的改变之间存在特定的关系，则有可能确定与痛性膀胱综合征相关的慢性膀胱和/或盆腔疼痛的药物治疗的新的分子靶点。

Patients with painful bladder syndromes such as interstitial cystitis (IC) characterized by urinary frequency, urgency, and bladder pain often exhibit urethral or pelvic pain. It is also documented that peripheral nerve injury in the pelvis may contribute to the emergence of bladder and/or pelvic pain because surgical manipulation of visceral organs is known to be a risk factor for the IC, and also often leads to aggravation of existing symptoms or onset of new symptoms in patients with pelvic pain. The urethra, urethral sphincter muscles and the pelvic floor are innervated by a subset of visceral (pelvic and hypogastric) and somatic (pudendal) afferent fibers which are a more diverse population (C, Asigma and Abeta-fibers; possibly Aalpha-fibers) than those innervating the urinary bladder (C and Asigma-fibers). However, little is known about their functional characteristics and changes under chronic pathological conditions including tissue inflammation or nerve injury that may result in chronic urethral or pelvic pain. Thus, in this research project, electrophysiologic, pharmacologic, molecular and neurochemical techniques will be used to examine the characteristics of urethral afferent neurons and somatic afferent neurons in the pudendal nerve. We are particularly interested in characterizing membrane properties of these afferent neurons, and also in identifying how the chemical mediators or pathology alter ion channel and receptor properties, leading to neuronal hyperexcitability. Several hypotheses will be tested: (1) Multiple subtypes of afferent neurons can be identified based on their functional and morphological properties including tetrodotoxin-resistant Na+ channels, slow-inactivating transient K+ channels, vanilloid receptors (VR1) sensitive to capsaicin, and immunoreactivity against specific cellular markers such as neurofilament or isolectin-B4, (2) Chronic inflammation of the urethra/pelvic floor or direct injury to the pudendal nerve alters the expression of ion channels or neurotransmitter mechanisms in afferent neurons, resulting in hyperexcitability of these neurons. These changes might be different from those that we have been recently identified in bladder afferent neurons, (3) Functional changes in urethral afferent neurons or pudendal afferent neurons under chronic pathological conditions can induce bladder and/or urethral hyperactivities by reorganizing viscerosomatic reflex activities. The long-term objectives of the research program are to understand the mechanisms by which irritating or nerve-injuring stimuli in pelvic organs induce phenotypic changes in their afferent pathways and thereby trigger chronic pain in the pelvis. If a specific relation is found between different pathology and alteration in ion channel or receptor properties/expression, it is possible to identify new molecular target of drug therapy for chronic bladder and/or pelvic pain associated with painful bladder syndromes.