Afferent plasticity underlying urethral and pelvic pain

描述（由申请人提供）：由于目前治疗下尿路疼痛疾病（LUT）的选择有限，如间质性膀胱炎（1C）或慢性盆腔疼痛综合征（CPPS），因此对开发新的治疗策略有很大的需求。美国国立卫生研究院资助“尿道和骨盆疼痛的传入可塑性”R01 DK57267, 1999年9月1日- 2003年8月31日，我们发现；(1)通往膀胱/近端尿道的内脏神经通路和通往外尿道括约肌(EUS)/盆底的躯体神经通路的传入纤维种群存在相当大的异质性；(2)膀胱/尿道组织炎症和体细胞阴部神经损伤可由于不同类型电压门控K+电流的减少而诱发膀胱/尿道c纤维传入高兴奋性相关的亢进。因此，本项目的目标是进一步确定与LUT疼痛相关的传入高兴奋性的诱导机制，特别是关注c纤维传入事件（即肽能和非肽能群体）的作用和神经营养因子依赖性调节。我们将首先研究核糖体失活毒素皂苷与隔离素B4结合的作用，从理论上讲，它可以通过ib4结合的非肽能c纤维传入途径抑制传入传递。这将使我们能够确定非肽能c纤维传入在LUT不同区域引起的疼痛条件下的功能作用。其次，我们将探讨两种不同的神经营养因子（NGF和GDNF）在LUT疼痛中c纤维高兴奋性的出现中的调节作用，因为据报道这两种因子分别调节肽能和非肽能c纤维传入通路的功能特性。第三，我们将试图阐明导致c -纤维高兴奋性的电压门控K+ (Kv)通道的分子特性，因为在我们之前的研究中，Kv通道的表达改变被证明有助于LUT疼痛条件下的c -纤维高兴奋性。使用尿道或骨盆疼痛动物模型的具体目的是：1)研究使用皂苷偶联物靶向非肽能性c -纤维传入通路对LUT疼痛状况的影响；II)研究NGF/GDNF及其抗体对LUT疼痛状况的影响；III)确定LUT传入神经元中Kv通道亚基的表达变化及其与K+电流亚型减少和c -纤维传入神经元高兴奋性的相关性。研究计划的长期目标是确定LUT疼痛状况的详细机制和新的有效治疗靶点。这被认为是IC/CPPS患者泌尿系统护理的重中之重。

DESCRIPTION (provided by applicant): Because of current, limited options for treating painful disorders in the lower urinary tract (LUT) such as interstitial cystitis (1C) or chronic pelvic pain syndrome (CPPS), there is a great demand for the development of new treatment strategy. Supported by NIH grant "Afferent plasticity underlying urethral and pelvic pain" R01 DK57267, 09/01/1999- 08/31/2003, we found that; (1) there is a considerable heterogeneity in afferent fiber populations in visceral neural pathways to the bladder/proximal urethra and somatic neural pathways to the external urethral sphincter (EUS)/pelvic floor, and (2) tissue inflammation of bladder/urethra and nerve injury of somatic pudendal nerves can induce bladder/urethral hyperactivity associated with C-fiber afferent hyperexcitability due to a reduction in different types of voltage-gated K+ currents. Thus, the goals of this proposed project are to further identify the mechanisms inducing afferent hyperexcitability related to LUT pain, especially focusing on the role and neurotrophic factor-dependent regulation of C-fiber afferents (i.e., peptidergic and non-peptidergic populations). We will first examine the effects of the ribosome-inactivating toxin saporin conjugated with isolectin B4, which can theoretically suppress afferent transmission via IB4-binding, non-peptidergic C-fiber afferent pathways. This will allow us to identify the functional role of non-peptidergic C-fiber afferents in pain conditions arising from different regions of the LUT. Secondly, we will explore the regulatory role of two different neurotrophic factors (NGF and GDNF) in the emergence of C-fiber hyperexcitability involved in LUT pain since these two factors reportedly modulate the functional properties of peptidergic and non-peptidergic C-fiber afferent pathways, respectively. Thirdly, we will seek to elucidate molecular identities of voltage-gated K+ (Kv) channels responsible for C-fiber hyperexcitability since altered expression of Kv channels was shown to contribute to C-fiber hyperexcitability in LUT pain conditions in our previous study. The Specific Aims of this proposal using animals models of urethral or pelvic pain are: I) to investigate the effects of targeting non-peptidergic C-fiber afferent pathways on LUT pain conditions using saporin conjugates; II) to investigate the effects of NGF/GDNF and their antibodies on LUT pain conditions; and III) to identify the changes in expression of Kv channel subunits in LUT afferent neurons and the correlation with a reduction of K+ current subtypes and C-fiber afferent neuron hyperexcitability. The long-term objectives of the research program are to identify the detailed mechanisms and new, effective therapeutic targets for pain conditions in the LUT. This is recognized as a high priority in the urologic care of patients with IC/CPPS.