Characterization of Hypogastric Afferent Pathway Involved in Urinary Bladder Function and Dysfunction

项目摘要 非伤害性AG纤维传入介导排尿反射和膀胱充盈的正常感觉 在骨盆神经中。虽然盆腔C纤维传入通常对膀胱扩张没有反应，但膀胱 刺激/感染使这些沉默的盆腔C-纤维对膀胱扩张敏感，导致尿路 紧迫感、频发率和引起膀胱痛。除骨盆神经外，腹下神经还 支配膀胱和腹下传入纤维，对膀胱扩张/刺激作出反应。不幸的是， 这些传入神经在控制排尿中的作用被打折扣，因为双侧横断HGNs没有 对正常生理性膀胱排尿的影响。然而，临床观察显示，HGN的传入 会导致人类的内脏疼痛和膀胱疼痛。我们最近发现，HGN还含有 “沉默的”纤维，在正常情况下对膀胱扩张基本不反应，但对 在膀胱受到化学刺激后，对这些压力做出反应。这表明这些纤维可能起到了 在病理性膀胱疾病中的关键作用，如膀胱过度活动(OAB)或间质性膀胱炎/膀胱痛 综合征(IC/BPS)，两者的临床表现均为尿急、尿频，与IC/BPS一起表现为膀胱 伴随的疼痛。目前，我们对外围设备和设备的基本组织结构的认识存在差距 控制下尿路的中枢神经通路，尤其是与HGN有关的。初步数据 结果表明，电刺激HGN传入细胞可降低化学致癌动物的膀胱容量。 刺激性膀胱(0.25%醋酸)，但不是非刺激性膀胱，提示HGN伤害性感受器相互作用 直接或间接地，与驱动膀胱病理的盆腔C纤维通路有关。为了加深我们的理解 在调控膀胱病理的伤害性通路中，我们假设腹下神经 痛觉感受器通过汇聚盆腔调节膀胱刺激时的过度活动 脊髓和/或大脑中的神经伤害性通路。为了测试这一概念，我们将从解剖学上 并对HGN内伤害性膀胱传入通路的中枢投射进行了功能表征 麻醉猫，电生理方法，c-fos示踪和fmri成像。完成拟议的 研究计划将揭示HGN传入通路参与病理生理机制 潜在的膀胱功能障碍和潜在的新诊断和治疗策略。

Project Summary The micturition reflex and normal sensation of bladder filling are mediated by non-nociceptive AG-fiber afferents in the pelvic nerve. While pelvic C-fiber afferents do not normally respond to bladder distension, bladder irritation/infection sensitizes these silent pelvic C-fibers to be responsive to bladder distension, causing urinary urgency, frequency and inducing bladder pain. In addition to the pelvic nerve, the hypogastric nerve (HGN) also innervates the bladder and hypogastric afferent fibers respond to bladder distention/irritation. Unfortunately, the role of these afferents in the control of micturition was discounted because bilateral transection of HGNs has no effect on normal physiological bladder voiding. Clinical observations have revealed, however, that HGN afferents contribute to visceral pain and bladder pain in humans. We have recently discovered that the HGN also contains “silent” fibers that are basally unresponsive to bladder distension under normal conditions but are sensitized to respond to these pressures after chemical irritation of the bladder. This suggests that these fibers may play a key role in pathological bladder disorders such as Overactive Bladder (OAB) or Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS), both of which present clinically as urinary urgency, frequency, and, with IC/BPS, bladder associated pain. At present, there is a gap in our understanding of the basic organization of the peripheral and central neural pathways controlling the lower urinary tract, especially in relation to the HGN. Preliminary data shows that electrical stimulation of HGN afferents can decrease bladder capacity in animals with chemically irritated bladders (0.25% acetic acid) but not non-irritated bladders, suggesting HGN nociceptors interact, either directly or indirectly, with the pelvic C-fiber pathways that drive bladder pathology. To further our understanding of the nociceptive pathways regulating bladder pathology, we hypothesize that hypogastric nerve nociceptors modulate bladder overactivity during bladder irritation through a convergence with pelvic nerve nociceptive pathways in the spinal cord and/or the brain. To test this concept, we will anatomically and functionally characterize the central projections of the nociceptive bladder afferent pathway in the HGN using anesthetized cats, electrophysiological methods, c-fos tracing and fMRI imaging. Completion of the proposed Research Plan will reveal the involvement of the HGN afferent pathway in the pathophysiological mechanisms underlying bladder dysfunction and potential new diagnostic and treatment strategies.