Receptor Selective Spinal Analgesia

描述（由申请人提供）：疼痛信号进入脊髓中的神经系统，在那里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的处理过程是如何出错的，导致持续的疼痛，而没有刺激，当皮肤被轻轻触摸时会产生灼痛。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后，无论是在战场上，在平民生活中，还是在大手术中。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，特别是剖腹产，但很少引起慢性疼痛，这表明在此期间有一种保护机制。啮齿类动物在分娩时进行手术后也不会出现慢性疼痛，初步研究表明，这是由于下丘脑向下的神经将荷尔蒙催产素释放到脊髓中。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，该基金将进行3种类型的研究。第一组研究将在大鼠中使用特定的治疗方法，这些方法可以防止下丘脑中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通路在保护脊髓免受物理创伤引起的慢性疼痛时发生的疼痛和神经化学变化方面的作用。要做到这一点，手术将在大鼠和他们的行为进行测量，并在他们的脊髓组织的蛋白质和细胞结构将被检查。第二组研究将测试分娩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防止慢性疼痛。为了做到这一点，将在麻醉的动物中进行感觉神经的记录，以首先了解受伤后轻微触摸的疼痛是否是由于它们发出的异常信号。然后将确定分娩和催产素对这些感觉神经的影响。第三组研究将在新妈妈身上测试，与没有孩子的女性相比，使用辣椒素霜（一种暂时性疼痛敏感的模型）后皮肤上的灼热和过敏反应是否会减少。在FDA的监督下，我们还将测试将催产素注射到男性和女性的脊柱空间中的安全性，并确定它是否能在正常志愿者和慢性腰痛患者的实验条件下减轻疼痛和超敏反应。 公共卫生相关性：如果我们要防止慢性疼痛在战争或平民受伤后发展，我们需要更好地了解它发生的过程和保护它的条件。该基金探索了临床观察，即分娩期间的创伤很少导致慢性疼痛，以了解这种保护并将其应用于其他环境。这些结果可能会改善我们对慢性疼痛的治疗，并提供一种新的方法来预防物理创伤后发生的慢性疼痛。

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. PUBLIC HEALTH RELEVANCE: If we are to prevent chronic pain from developing after war or civilian injuries we need to better understand the process by which it occurs and conditions which protect against it. This grant explores the clinical observation that trauma during childbirth very rarely causes chronic pain in order to understand this protection and apply it to other settings. The results may improve our treatment of chronic pain and offer a new approach to prevent chronic pain occurring after physical trauma.