Receptor Selective Spinal Analgesia

描述(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，导致在没有刺激的情况下持续疼痛，以及当皮肤被轻轻触摸时会产生灼痛。最终目标是找到治疗慢性疼痛的更好方法，并在受伤时防止它。慢性疼痛发生在身体创伤之后，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困难，拟议的工作涉及NIGMS和NIH了解和更好地治疗包括疼痛在内的中枢神经系统疾病的使命。分娩也会造成身体创伤，特别是剖腹产，但很少会引起慢性疼痛，这表明在这一时期有一种保护机制。啮齿动物也不会在手术后出现慢性疼痛，如果是在分娩时进行的，初步研究表明这是由于从下丘脑下降的神经向脊髓释放激素催产素所致。为了确定这种针对身体创伤的慢性疼痛的重要保护机制，这笔赠款将进行3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，既可以防止分娩时下丘脑中的催产素神经受到刺激，也可以防止脊髓中催产素本身的作用，以更好地了解这种下行催产素途径在保护脊髓免受疼痛和神经化学变化方面的作用，当身体创伤导致慢性疼痛时，脊髓中会发生这种变化。为此，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。第二组研究将测试脊髓中的产期和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，将在麻醉的动物身上进行感觉神经的记录，以首先了解受伤后轻微触摸造成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，使用辣椒素乳膏对皮肤的灼热和过敏反应是否会减少。辣椒素乳膏是一种暂时的疼痛敏感模型。我们还将在FDA的监督下，测试将催产素注射到男性和女性脊柱间隙的安全性，并在实验条件下确定它是否可以减轻正常志愿者和慢性下腰痛患者的疼痛和过敏症。 与公共卫生相关：如果我们要防止战后慢性疼痛的发展或平民受伤，我们需要更好地了解它发生的过程和防止它的条件。这笔赠款探索了临床观察，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。这一结果可能会改善我们对慢性疼痛的治疗，并为预防身体创伤后发生的慢性疼痛提供一种新的方法。

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.