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

描述（由申请人提供）：每年有数百万患者接受外科手术，许多患者会出现持续数月或数年的中度至重度疼痛。手术后慢性疼痛（CPAS）现在被认为是一个重大的公共卫生问题，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cpa的标准医疗保健。这部分是由于对术后疼痛从手术部位愈合后的急性疼痛转变为慢性疼痛状态的机制了解不完全。最近的临床研究表明，下降抑制系统受损可能使个体易患CPAS。基于这一临床观察，我们开发了一种涉及大鼠脊髓去甲肾上腺素能纤维耗竭的新型CPAS模型。单侧足底切开前去甲肾上腺素能张力的降低导致同侧和对侧机械性异常痛的延长，以及双侧小胶质细胞和星形胶质细胞的激活，但对基线伤害感觉没有影响。有趣的是，慢性给药22肾上腺素能受体激动剂克仑特罗可以防止该模型中观察到的同侧和对侧机械异常性疼痛的延长。在提案的具体目标1中，我们将通过对几种行为措施进行长期评估来验证该模型，包括自发保护、机械超敏反应和受损的食物强化操作反应。对这些行为测量的同时评估将为未来的研究确定最相关的终点，并允许对这些终点之间的动物关系进行新的分析。在Specific Aim 2中，我们将结合体内和体外药理学、免疫组织化学和生化方法来研究手术切口后去甲肾上腺素能张力降低导致机械超敏反应和神经胶质活化增强的机制。在Aim 3中，我们将以初步数据为基础，通过确定该化合物的作用部位以及适当的治疗时机来证明克仑特罗的保护作用，以预防或逆转该模型中与疼痛相关的行为。我们的长期目标是利用这个模型开始确定手术后从急性到慢性疼痛转变的关键细胞机制，并利用这些信息确定可以快速转化为临床的新治疗策略。

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.