AFFERENT PLASTICITY UNDERLYING URETHRAL AND PELVIC PA

膀胱疼痛综合征如间质性膀胱炎（IC）患者的特征是尿频、尿急和膀胱疼痛，通常表现为尿道或盆腔疼痛。 还记录了骨盆周围神经损伤可能导致膀胱和/或骨盆疼痛的出现，因为已知内脏器官的手术操作是IC的风险因素，并且还通常导致骨盆疼痛患者的现有症状加重或新症状的发作。尿道、尿道括约肌和骨盆底由内脏（骨盆和腹下）和躯体（阴部）传入纤维的子集支配，这些传入纤维是比支配膀胱的纤维（C和Asigma纤维）更多样化的群体（C、Asigma和Abeta纤维;可能是Aalpha纤维）。然而，很少有人知道他们的功能特点和慢性病理条件下的变化，包括组织炎症或神经损伤，可能会导致慢性尿道或盆腔疼痛。 因此，本研究拟采用电生理、药理学、分子生物学和神经化学等技术，对尿道传入神经元和阴部神经躯体传入神经元的特性进行研究。 我们特别感兴趣的是表征这些传入神经元的膜特性，以及确定化学介质或病理学如何改变离子通道和受体特性，导致神经元过度兴奋。将检验几个假设：（1）传入神经元的多种亚型可以基于它们的功能和形态学特性来鉴定，包括河豚毒素抗性Na+通道、缓慢失活的瞬时K+通道、对辣椒素敏感的香草素受体（VR 1）以及针对特定细胞标记物如神经丝或异凝集素-B4的免疫反应性，（2）尿道/骨盆底的慢性炎症或阴部神经的直接损伤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。 （3）慢性病理状态下尿道或阴部传入神经元的功能改变可通过重组内脏躯体反射活动而引起膀胱和/或尿道活动亢进。该研究计划的长期目标是了解盆腔器官中刺激性或神经损伤性刺激诱导其传入途径表型变化的机制，从而引发盆腔慢性疼痛。如果在不同的病理学和离子通道或受体特性/表达的改变之间发现特定的关系，则有可能确定与疼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.