Receptor Selective Spinal Analgesia

描述（由申请人提供）：疼痛信号进入脊髓的神经系统，这些信号在被传输到大脑之前被处理。这项资助旨在了解受伤后这种处理是如何出错的，导致没有刺激的持续疼痛和轻微触摸皮肤时的灼痛感。最终目标是找到更好的方法来治疗慢性疼痛，并在受伤时预防它。慢性疼痛发生在身体创伤之后，无论是在战场上，平民生活中，还是大手术。慢性疼痛的治疗和预防仍然很困难，拟议的工作解决了NIGMS和NIH的使命，以了解和更好地治疗中枢神经系统疾病，包括疼痛。分娩也会造成身体创伤，尤其是剖宫产，但很少会引起慢性疼痛，这表明在这一时期存在一种保护机制。如果在分娩时进行手术，啮齿动物也不会在手术后出现慢性疼痛。初步研究表明，这是由于下丘脑的神经向脊髓释放了一种名为催产素的激素。为了确定这种重要的保护机制，防止身体创伤引起的慢性疼痛，这笔拨款将进行三种类型的研究。第一组研究将在大鼠身上使用特定的治疗方法，既可以防止下丘脑的催产素神经在分娩时受到刺激，也可以防止催产素本身在脊髓中的作用，以更好地了解这种下行催产素途径在防止疼痛和神经化学变化方面的作用，这种变化发生在脊髓中，当身体创伤引起的慢性疼痛发展时。为了做到这一点，将在大鼠身上进行手术，测量它们的行为，并检查它们脊髓组织中的蛋白质和细胞结构。第二组研究将测试产褥期和脊髓中的催产素是否通过改变来自皮肤的感觉神经的活动来预防慢性疼痛。为了做到这一点，麻醉动物的感觉神经将被记录下来，以首先了解受伤后轻触引起的疼痛是否是由于它们发出的异常信号。然后分娩和催产素对这些感觉神经的影响就决定了。第三组研究将在新妈妈中测试，与没有孩子的女性相比，使用辣椒素乳膏（一种暂时疼痛敏感的模型）后皮肤上的灼烧和过敏反应是否会减少。我们还将在FDA的监督下，测试在男性和女性的脊柱间隙注射催产素的安全性，并确定在正常志愿者和慢性腰痛患者的实验条件下，它是否能减轻疼痛和过敏。

DESCRIPTION (provided by applicant): Pain signals enter the nervous system in the spinal cord, where these signals are processed before being transmitted to the brain. This grant seeks to understand how that processing goes awry after injury, leading to constant pain without stimulation and burning pain when the skin is lightly touched. The ultimate goals are to identify better ways to treat chronic pain and also to prevent it at the time of injury. Chronic pain occurs after physical trauma, whether on the battlefield, in civilian life, or from major surgery. Treatment and prevention of chronic pain remains difficult, and the proposed work addresses the mission of NIGMS and the NIH to understand and better treat disorders of the central nervous system, including pain. Childbirth, which also causes physical trauma, particularly by cesarean delivery, only rarely causes chronic pain, suggesting a protective mechanism during this period. Rodents also fail to develop chronic pain after surgery if it is performed at the time of delivery, and preliminary studies suggest this is due to release of the hormone, oxytocin, into the spinal cord by nerves which descend from the hypothalamus. To determine the mechanisms for this important protection against chronic pain from physical trauma, this grant will perform 3 types of studies. The first set of studies will use specific treatments in rats which either prevent the oxytocin nerves in the hypothalamus from being stimulated at the time of delivery or to prevent the action of oxytocin itself in the spinal cord to better understand the role of this descending oxytocin pathway in protection against pain and neurochemical changes which occur in the spinal cord when chronic pain from physical trauma develops. To do this surgery will be performed in rats and their behavior measured, and proteins and cell structure in their spinal cord tissue will be examined. The second set of studies will test whether the delivery period and oxytocin in the spinal cord protect against chronic pain by changing the activity of sensory nerves coming from the skin. To do this recordings from sensory nerves will be made in anesthetized animals to first understand whether pain from light touch after injury is due to an abnormal signal from them. Then the effect of delivery and oxytocin will be determined on these sensory nerves. The third set of studies will test in new mothers whether the burning and hypersensitive response on the skin from application of capsaicin cream, a model of temporary pain sensitivity, are reduced compared to women without children. We will also, under FDA oversight, test the safety of injecting oxytocin into the spinal space of men and women and determine whether it reduces pain and hypersensitivity in experimental conditions in normal volunteers and in those with chronic low back pain.