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，许多患者将出现持续数月和数年的中度至重度疼痛。手术后慢性疼痛（CPAS）现在被认为是一个主要的公共卫生问题，可以对一个人的生活质量产生深远的影响。目前，没有专门用于治疗或预防CPAS的标准医疗护理。这部分是由于对术后疼痛从手术部位愈合后缓解的急性现象转变为慢性疼痛状态的机制了解不完整。最近的临床研究表明，受损的下行抑制系统可能使个体容易患上CPAS。基于这一临床观察，我们开发了一种新的CPAS模型，涉及大鼠脊髓去甲肾上腺素能纤维的耗竭。单侧足底切口前去甲肾上腺素能张力降低导致同侧和对侧机械性异常性疼痛延长以及双侧小胶质细胞和星形胶质细胞活化，而对基线伤害性感受无影响。有趣的是，长期服用肾上腺素能受体激动剂克仑特罗可以防止在该模型中观察到的长时间同侧和对侧机械性异常性疼痛。在提案的具体目标1中，我们将通过对几种行为指标进行长期评估来验证该模型，这些指标包括自发性防卫、机械性超敏反应和受损的食物强化操作性反应。这些行为指标的同时评价将允许识别未来研究的最相关终点，并允许进行新的分析，以检查这些终点之间的动物关系。在特定目标2中，我们将使用体内和体外药理学、免疫组织化学和生物化学方法的组合来检查去甲肾上腺素能张力降低导致手术切口后机械超敏反应和神经胶质活化增强的机制。在目标3中，我们将建立在初步数据的基础上，通过确定该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，以预防或逆转该模型中的疼痛相关行为。我们的长期目标是使用该模型开始确定负责手术后从急性疼痛转变为慢性疼痛的关键细胞机制，并使用此信息来确定可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.