AFFERENT PLASTICITY UNDERLYING URETHRAL AND PELVIC PA

膀胱疼痛综合征的患者，如间质性膀胱炎（IC），以尿频、尿急和膀胱疼痛为特征，常表现为尿道或盆腔疼痛。也有文献表明，骨盆周围神经损伤可能导致膀胱和/或盆腔疼痛的出现，因为已知内脏器官的手术操作是IC的危险因素，并且还经常导致盆腔疼痛患者现有症状的加重或新症状的出现。尿道、尿道括约肌和盆底受内脏（盆腔和下胃）和躯体（阴部）传入纤维的支配，这些传入纤维比支配膀胱的传入纤维（C和Asigma-纤维）更为多样化（C、Asigma和β -纤维，也可能是α -纤维）。然而，在组织炎症或神经损伤等可能导致慢性尿道或盆腔疼痛的慢性病理条件下，它们的功能特征和变化知之甚少。因此，本研究将运用电生理、药理学、分子和神经化学等技术，研究阴部神经的尿道传入神经元和躯体传入神经元的特征。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如何改变离子通道和受体特性，导致神经元的高兴奋性。将测试几个假设：(1)根据传入神经元的功能和形态特征，包括抗河河鱼毒素的Na+通道、缓慢失活的瞬时K+通道、对辣椒素敏感的香兰素受体（VR1）以及对特定细胞标志物（如神经丝或isolecin - b4）的免疫反应性，可以鉴定出传入神经元的多个亚型。(2)尿道/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的离子通道表达或神经递质机制，导致传入神经元的高兴奋性。(3)慢性病理状态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脏器体反射活动诱导膀胱和/或尿道亢进。研究计划的长期目标是了解骨盆器官的刺激或神经损伤刺激诱导其传入通路表型变化的机制，从而引发骨盆慢性疼痛。如果发现不同病理与离子通道或受体性质/表达改变之间的特定关系，就有可能确定与膀胱疼痛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.