Pelvic Visceral Interaction Following Spinal Cord Injury

脊髓损伤后的骨盆内脏相互作用

基本信息

  • 批准号:
    9114883
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-06-01 至 2017-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Spinal cord injury (SCI) creates a serious health problem due to interruption of communication between supraspinal levels and the spinal cord circuitry. As such, there is loss of conscious sensation below the level of the lesion and loss of descending control of the spinal cord circuitry Both neurogenic bowels and bladders resulting from lesions above T12 are characterized by visceral hyperreflexia and outlet dyssynergia. For the bladder, this results in frequent high pressure non- voiding contractions, while in the bowel there is an increase in wall muscle tone. This activity is thought to arise from uninhibited C-fiber nociceptive mechanosensitive reflexes due to the loss of descending inhibition. Indeed, SCI has also been shown to result in heightened afferent responses in other organ systems distal to the lesion. Thus we suspect that the release of C-fibers from descending inhibitory control, "C-fiber release", is responsible for the time-dependent development of hyperreflexic neurogenic bladder and bowel in high level SCI and may also result in a chronic state of neurogenic inflammation due to uninhibited dorsal root reflexes in response to neurogenic activity. Moreover, release of inflammatory mediators from C-fibers would further sensitize these same afferents (homosensitization). Thus, within each organ, a positive escalation of peripheral and central sensitization may occur and we propose that the resultant chronic inflammatory state is responsible for much of the end organ tissue damage. Additionally, a significant amount of work from our laboratory and others supports the notion of pelvic visceral cross-sensitization (heterosensitization) in spinally intact animals, such that irritation insult of one pelvic organ results in neurogenic reflex irritation in neighboring organs innervated by the same spinal levels, and that this is also mediated by C-fibers. We envision that this process is facilitated by C-fiber release. Thus, we predict that unde conditions of SCI and C-fiber release, pelvic organ insults (e.g. infection) may more readily result in neurogenic inflammation of neighboring organs. For example, the repeated urinary tract infections common in SCI patients are predicted to easily result in a reflex neurogenic inflammation of the distal colon. Such effects may be occult in nature due to lack of pathogen in the cross-sensitized organ and lack of conscious sensation of discomfort or pain. As most of the nociceptive C-fibers of hollow viscera reside in the mucosa and submucosa, it is a common outcome of neurogenic inflammation to result in epithelial barrier dysfunction, which may have serious health consequences. Our overarching hypothesis is that interruption of descending control results in C-fiber release which in turn results in a sensitization of C-fiber nociceptors n each organ and amplification of responses to irritative stimuli in both the insulted and uninsulted organ. We will study homo- and heterosensitization of pelvic organ C-fiber afferents before and after acute spinal anesthesia (to eliminate descending control) in the same animals, and between chronic SCI animals and controls. We predict that threshold for noxious distension will be lowered following C-fiber release and that pelvic organ homo- and heterosensitization due to chemical peripheral irritation of one organ will likewise be enhanced. We therefore further expect that C-fiber sensitization and the degree of heterosensitization responsiveness increases progressively in parallel to the progressive development of C-fiber control of the sacral parasympathetic nucleus in chronic SCI.
 描述(由申请人提供): 由于脊髓上层和脊髓回路之间的通讯中断,脊髓损伤 (SCI) 会造成严重的健康问题。因此,病变水平以下的意识感觉丧失,脊髓回路的下行控制丧失。T12 以上病变引起的神经源性肠和膀胱的特征是内脏反射亢进和出口协同失调。对于膀胱,这会导致频繁的高压非排尿性收缩,而在肠道中,壁肌张力增加。这种活动被认为是由于下行抑制丧失而不受抑制的 C 纤维伤害感受机械敏感反射引起的。事实上,SCI 也被证明会导致病变远端其他器官系统的传入反应增强。因此,我们怀疑 C 纤维从下行抑制控制中释放出来,即“C 纤维释放”,是高水平 SCI 中反射亢进的神经源性膀胱和肠的时间依赖性发育的原因,并且还可能由于对神经源性活动的反应不受抑制的背根反射而导致神经源性炎症的慢性状态。此外,C 纤维释放的炎症介质将进一步使这些相同的传入神经变得敏感(同质化)。因此,在每个器官内,可能会发生外周和中枢敏化的积极升级,我们认为由此产生的慢性炎症状态是造成大部分终末器官组织损伤的原因。此外,我们实验室和其他实验室的大量工作支持完整脊柱中骨盆内脏交叉致敏(异质致敏)的概念 动物,例如对某一盆腔器官的刺激损伤会导致神经源性反射刺激 邻近器官受同一脊髓水平支配,并且这也是由 C 纤维介导的。我们预计 C 纤维的释放会促进这一过程。因此,我们预测在 SCI 和 C 纤维释放的情况下,盆腔器官损伤(例如感染)可能更容易导致邻近器官的神经源性炎症。例如,SCI患者常见的反复尿路感染预计很容易导致远端结肠的反射性神经源性炎症。由于交叉致敏器官中缺乏病原体并且缺乏不适或疼痛的有意识感觉,这种效应本质上可能是隐秘的。由于中空内脏的大部分伤害性 C 纤维驻留在粘膜和粘膜下层,神经源性炎症的常见结果是导致上皮屏障功能障碍,这可能会产生严重的健康后果。 我们的总体假设是,下降控制的中断会导致 C 纤维释放,进而导致每个器官中的 C 纤维伤害感受器变得敏感,并放大受侮辱和未受侮辱的刺激性刺激的反应 器官。我们将研究同一动物急性脊髓麻醉(以消除下行控制)前后盆腔器官 C 纤维传入的同源和异源敏感性,以及慢性 SCI 动物和对照之间的情况。我们预测,C 纤维释放后,有害性扩张的阈值将降低,并且由于某一器官的化学外周刺激而导致的盆腔器官同质和异质敏感性同样会增强。因此,我们进一步预计,慢性 SCI 中 C 纤维敏化和异质敏化反应程度与 C 纤维对骶副交感神经核控制的逐渐发展平行。

项目成果

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MATTHEW O FRASER其他文献

MATTHEW O FRASER的其他文献

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{{ truncateString('MATTHEW O FRASER', 18)}}的其他基金

Neurostimulation for lower motor neuron bowel syndrome due to incomplete lower motor neuron injury
神经刺激治疗因不完全下运动神经元损伤引起的下运动神经元肠综合征
  • 批准号:
    10368668
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Neurostimulation for lower motor neuron bowel syndrome due to incomplete lower motor neuron injury
神经刺激治疗因不完全下运动神经元损伤引起的下运动神经元肠综合征
  • 批准号:
    10623142
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Cell-based Therapy for Neurogenic Bladder following Spinal Cord Injury
脊髓损伤后神经源性膀胱的细胞疗法
  • 批准号:
    8399231
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Diabetic Urethral Pathophysiology and Afferent Therapy
糖尿病尿道病理生理学和传入治疗
  • 批准号:
    6908909
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
Diabetic Urethral Pathophysiology and Afferent Therapy
糖尿病尿道病理生理学和传入治疗
  • 批准号:
    7095831
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
Diabetic Urethral Pathophysiology and Afferent Therapy
糖尿病尿道病理生理学和传入治疗
  • 批准号:
    6460437
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
Diabetic Urethral Pathophysiology and Afferent Therapy
糖尿病尿道病理生理学和传入治疗
  • 批准号:
    6806063
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:

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