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

参与膀胱功能和功能障碍的下腹传入通路的特征

• 批准号: 10711706
• 负责人: JONATHAN M BECKEL
• 金额: $ 39.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711706
• 关键词: Acetic Acids; Afferent Pathways; Anatomy; Anesthesia procedures; Animals; Area; Automobile Driving; Bilateral; Bladder; Bladder Control; Bladder Diseases; Bladder Dysfunction; Brain; C Fiber; Central Nervous System; Chemicals; Clinical; Data; Devices; Electric Stimulation; Electrophysiology (science); Esthesia; Etiology; FOS gene; Felis catus; Fiber; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Human; Image; Infection; Inflammation; Interneurons; Interoception; Interstitial Cystitis; Irritants; Limb structure; Location; Lower urinary tract; Lumbar spinal cord structure; Maps; Mediating; Methods; Microelectrodes; Micturition Reflex; Nerve; Neural Pathways; Nociception; Nociceptors; Overactive Bladder; Pain; Pathologic; Pathology; Pathway interactions; Pattern; Pelvic Pain; Pelvis; Peripheral; Peripheral Nerve Stimulation; Physiological; Play; Reflex action; Research; Role; Sacral nerve; Saline; Sensory; Site; Spinal Cord; Stimulus; Stretching; Techniques; Testing; Travel; Urination; Urine; Visceral pain; afferent nerve; bladder pain; diagnostic strategy; diagnostic tool; experimental study; irritation; micturition urgency; neuroregulation; novel diagnostics; novel therapeutics; pressure; treatment strategy

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.

项目摘要 排尿反射和膀胱充盈的正常感觉是由非伤害性的AG纤维传入介导的 骨盆神经虽然骨盆C纤维传入通常不响应膀胱扩张，膀胱 刺激/感染使这些沉默的骨盆C纤维敏感，从而对膀胱扩张做出反应，引起尿失禁。 尿急、尿频和诱发膀胱疼痛。除了骨盆神经，腹下神经（HGN）也 神经支配膀胱和腹下传入纤维对膀胱扩张/刺激作出反应。可惜 这些传入神经在排尿控制中的作用被低估，因为双侧HGN的横断没有 对正常生理膀胱排尿的影响。然而，临床观察显示，HGN传入神经 导致人类内脏疼痛和膀胱疼痛。我们最近发现HGN还含有 在正常情况下对膀胱扩张基本无反应，但对膀胱扩张敏感的“沉默”纤维 在膀胱受到化学刺激后对这些压力作出反应。这表明，这些纤维可能发挥作用， 在病理性膀胱疾病（如膀胱过度活动症（OAB）或间质性膀胱炎/膀胱疼痛）中的关键作用 综合征（IC/BPS），这两种疾病在临床上表现为尿急、尿频，在IC/BPS的情况下，表现为膀胱 相关的疼痛。目前，我们对外围和外围的基本组织的理解存在差距， 控制下尿路的中枢神经通路，特别是与HGN有关。初步数据 表明HGN传入神经的电刺激可以降低化学性膀胱炎动物的膀胱容量， 刺激膀胱（0.25%乙酸），但不是非刺激膀胱，表明HGN伤害感受器相互作用，无论是 直接或间接地与驱动膀胱病理的盆腔C纤维通路。为了进一步了解 在调节膀胱病理的伤害性通路中，我们假设腹下神经 在膀胱刺激期间，伤害感受器通过与骨盆的会聚来调节膀胱过度活动。 脊髓和/或脑中的神经伤害感受路径。为了验证这一概念，我们将从解剖学角度 和功能特征的伤害性膀胱传入通路在HGN中的中枢投射， 麻醉猫，电生理学方法，c-fos示踪和fMRI成像。完成建议 研究计划将揭示HGN传入通路在病理生理机制中的参与 潜在的膀胱功能障碍和潜在的新的诊断和治疗策略。