Pelvic Visceral Interaction Following Spinal Cord Injury

 描述(由申请人提供)： 脊髓损伤(SCI)是一种严重的健康问题，其原因是脊髓上水平和脊髓回路之间的通讯中断。因此，病变平面以下会失去知觉，脊髓回路的下行控制也会丧失。T12以上病变引起的神经源性肠和膀胱的特点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无排尿收缩，而在肠道，壁肌张力增加。这种活动被认为是由不受抑制的C纤维伤害性机械敏感反射引起的，因为下行抑制的丧失。事实上，脊髓损伤也被证明导致损伤远端其他器官系统的传入反应增强。因此，我们推测，下行抑制控制中C纤维的释放，即“C纤维释放”，是高水平脊髓损伤后反射亢进的神经源性膀胱和肠道的时间依赖性发展的原因，也可能是由于对神经源性活动的无抑制的背根反射导致的慢性神经源性炎症状态。此外，C纤维释放的炎性介质会进一步敏化这些相同的传入物质(同敏)。因此，在每个器官内，外周和中枢敏化的积极升级可能发生，我们认为由此产生的慢性炎症状态是终末器官组织损伤的主要原因。此外，我们实验室和其他实验室的大量工作支持在脊柱完整的情况下盆腔内脏交叉敏化(异敏化)的概念。 动物，如对一个盆腔器官的刺激性侮辱导致神经源性反射性刺激 相邻器官由相同的脊髓节段支配，这也是由C纤维介导的。我们预计，C纤维的释放将促进这一过程。因此，我们预测在脊髓损伤和C纤维释放的条件下，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，脊髓损伤患者中常见的反复尿路感染被预测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没有病原体，也没有不适或疼痛的有意识感觉，这种影响在性质上可能是隐蔽的。由于中空脏器的大部分伤害性C纤维存在于粘膜和粘膜下层，神经源性炎症导致上皮屏障功能障碍是一种常见的结果，可能会造成严重的健康后果。我们的主要假设是，阻断下行控制导致C-纤维释放，进而导致每个器官的C-纤维伤害性感受器敏化，并放大受损者和未受损者对刺激性刺激的反应 管风琴。我们将在同一动物中，以及慢性脊髓损伤动物和对照组之间，研究急性脊麻前后盆腔器官C纤维传入的同种和异敏反应(以消除下行控制)。我们预测，在C纤维释放后，伤害性扩张的阈值将降低，由于一个器官的化学外周刺激而导致的盆腔器官同质性和异敏性也将同样增强。因此，我们进一步预计，在慢性脊髓损伤中，C纤维敏化和异敏反应程度与C纤维对骶骨副交感神经核控制的进行性发展平行地逐渐增加。

 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.