Mechanisms Involved in the Transition of Acute to Chronic Pain after Surgery

描述(申请人提供)：每年有数以百万计的患者接受外科手术，许多人会出现中到重度的疼痛，持续数月甚至数年。手术后慢性疼痛(CPAS)现在被认为是一个主要的公共卫生问题，它可以对一个人的生活质量产生深远的影响。目前，没有专门治疗或预防注册会计师的标准医疗服务。这在一定程度上是由于对术后疼痛从手术部位愈合到慢性疼痛状态后消失的急性现象的过渡机制的不完全了解。最近的临床研究表明，下行抑制系统受损可能使个体更容易患上CPA。在此临床观察的基础上，我们开发了一种新的CPAS模型，该模型涉及大鼠脊髓去甲肾上腺素能纤维的耗竭。单侧足底切开前去甲肾上腺素能张力降低导致同侧和对侧机械性痛觉超敏延长，双侧小胶质细胞和星形胶质细胞激活，而不影响基线伤害性感觉。有趣的是，22肾上腺素能受体激动剂克伦特罗的慢性给药阻止了在该模型中观察到的同侧和对侧延长的机械性异位痛觉。在该提案的具体目标1中，我们将通过对几种行为措施进行长期评估来验证这一模型，这些行为措施包括自发防御、机械超敏反应和受损的食物强化操作者反应。对这些行为测量的同时评估将允许为未来的研究识别最相关的终点，并允许新的分析来检查这些终点之间的动物关系。在具体目标2中，我们将使用体内和体外药理学、免疫组织化学和生化方法相结合的方法来研究手术切开后去甲肾上腺素张力降低有助于增强机械超敏反应和神经胶质细胞激活的机制。在目标3中，我们将建立在初步数据的基础上，通过确定这种化合物的作用部位以及适当的治疗时机来证明克伦特罗的保护作用，以防止或逆转该模型中的疼痛相关行为。我们的长期目标是利用这一模型开始识别导致手术后从急性疼痛向慢性疼痛转变的关键细胞机制，并利用这些信息确定可以迅速转化为临床的新的治疗策略。

DESCRIPTION (provided by applicant): Millions of patients each year undergo surgical procedures and many will develop moderate to severe pain which persists for months and years. Chronic pain after surgery (CPAS) is now recognized as a major public health concern which can have a profound impact on a person's quality of life. Currently, there is no standard medical care provided specifically to treat or prevent CPAS. This is due in part to an incomplete knowledge of the mechanisms responsible for the transition of postoperative pain from an acute phenomenon that resolves after the surgical site heals to a chronic pain state. Recent clinical studies show that impaired descending inhibitory systems may predispose individuals to CPAS. Building on this clinical observation, we developed a novel model of CPAS involving depletion of spinal noradrenergic fibers in rats. Reduction in noradrenergic tone prior to unilateral plantar incision resulted in a prolonged ipsilateral and contralateral mechanical allodynia as well as bilateral microglial and astrocyte activation without effects on baseline nociception. Intriguingly, chronic administration of the 22 adrenergic receptor agonist clenbuterol prevented the prolonged ipsilateral and contralateral mechanical allodynia observed in this model. In Specific Aim 1 of the proposal, we will validate this model by conducting long term assessment of several behavioral measures including spontaneous guarding, mechanical hypersensitivity, and impaired food-reinforced operant responding. The simultaneous evaluation of these behavioral measures will allow identification of the most relevant endpoints for future studies and allow novel analysis to examine within animal relationships between these endpoints. In Specific Aim 2 we will use a combination of in vivo and in vitro pharmacological, immunohistochemical, and biochemical methods to examine the mechanisms by which reduced noradrenergic tone contributes to enhanced mechanical hypersensitivity and glial activation following surgical incision. In Aim 3, we will build on preliminary data demonstrating a protective effect of clenbuterol by determining the site of action of this compound as well as the appropriate timing of therapy to prevent or reverse pain related behaviors in this model. Our long term objective is to use this model to begin to identify key cellular mechanisms responsible for the transition from acute to chronic pain following surgery and use this information to identify novel therapeutic strategies that can be rapidly translated into the clinic.