Persistent Mechanical Hypersensitivity in Rats: Biobehavioral Effects

描述(由申请人提供)：惊人的26%的美国人报告上个月疼痛持续超过一天，其中42%的人表示他们的疼痛持续了一年以上。尽管慢性疼痛问题的范围很广，但对从急性疼痛条件到持续性疼痛综合征的因果路径的了解或研究却很少。持续性疼痛的临床模型显示，急性疼痛的体验和慢性疼痛的发展过程具有很大的变异性，而临床前模型显示急性疼痛的体验或持续性疼痛的发展的变异性很小。这一新合作努力的长期目标是系统地利用已建立的临床前模型，该模型提供了研究持续性疼痛发展的易感性和弹性的机会。我们的总体假设是，生物行为因素，如睡眠中断和下丘脑-垂体-肾上腺(HPA)轴应激反应的改变，都是持续性疼痛条件发展的原因和结果。我们建议利用坐骨神经炎性神经炎(SIN)模型，该模型有利于分离手术创伤和疼痛起始，以及酵母多糖作为疼痛起始剂的可控性和可变性，以解决雄性大鼠的两个特定目标：(1)确定睡眠中断对持续性炎症诱导的机械超敏发展的影响。持续炎症诱导的机械过敏的发生和严重程度将在保持不受干扰的大鼠和那些在从第一次SIN导管酵母多糖注射的前一天开始的第一天的6小时内通过温和的处理而被破坏的大鼠之间进行比较。(2)确定HPA轴反应性在持续性炎症诱导的机械超敏反应中的作用及其对睡眠-觉醒行为的影响。将比较近交系HPA轴低反应Lewis和HPA轴高反应性Fischer 344大鼠，以及近交系Spraogue Dawley大鼠炎症诱导的持续性机械超敏反应的发生和严重程度及其对睡眠-觉醒行为的影响。这项拟议研究的意义涉及慢性疼痛的普遍性、疼痛和睡眠中断的高度关联性，以及之前识别与慢性疼痛发展相关的易感性和弹性因素的实验工作的匮乏。这项研究的创新之处在于采用了一种生态上有效的睡眠剥夺范式，并利用遗传上不同的大鼠品系来确定HPA轴响应性对持续性机械超敏反应发展和随后的睡眠改变的贡献。这项拟议研究的成功进行将提供一个平台，在此基础上开展研究，重点关注睡眠以外的功能结果，如运动、情绪和早期生活疼痛体验。女性的加入是下一步至关重要的一步。公共卫生报告最近报告慢性疼痛的患病率达到惊人的48%，而主要由神经性原因引起的疼痛报告为8%。尽管慢性疼痛问题的范围很广，但对从急性疼痛过渡到长期慢性疼痛的原因了解或研究却很少。这项拟议的研究与人类健康的相关性旨在找出哪些因素(如睡眠中断、对压力和焦虑的生物反应)会增加S患慢性疼痛的风险。

DESCRIPTION (provided by applicant): An alarming 26% of Americans report pain persisting for more than one day in the previous month and 42% of these individuals indicated that their pain lasted more than one year. Despite the enormous scope of the problem of chronic pain, there is minimal understanding or study of the causal pathways in the transition from acute pain conditions to persistent pain syndromes. Clinical models of persistent pain indicate large variability in the experience of acute pain and the course of chronic pain development, yet pre-clinical models demonstrate small variability in the experience of acute pain or the development of persistent pain. The long- term goal of this new collaborative effort is to systematically exploit an established pre-clinical model that offers the opportunity to study susceptibility to and resilience against persistent pain development. Our overarching hypothesis is that biobehavioral factors such as sleep disruption and altered hypothalamic-pituitary-adrenal (HPA) axis stress responsivity both contribute to and result from the development of persistent pain conditions. We propose to exploit the sciatic inflammatory neuritis (SIN) model, advantageous for separating the surgical insult from pain initiation, and the controllability and variability of the zymosan dose as pain initiator, to address two specific aims in male rats: (1) To determine the impact of sleep disruption on the development of persistent inflammation-induced mechanical hypersensitivity. The occurrence and severity of persistent inflammation- induced mechanical hypersensitivity will be compared between rats remaining undisturbed versus those whose sleep attempts are disrupted by gentle handling during the first 6 h after light onset each day from the day prior to the first SIN catheter zymosan infusion through the 10th and final daily zymosan infusion. (2) To determine the impact of HPA axis responsivity on the development of persistent inflammation-induced mechanical hypersensitivity and its consequent effects on sleep-wake behavior. The inbred HPA axis hyporesponsive Lewis and HPA axis hyper-responsive Fischer 344 rats, and the outbred Sprague Dawley rat will be compared for the occurrence and severity of inflammation-induced persistent mechanical hypersensitivity as well as its impact on sleep-wake behavior. The significance of the proposed study relates to the pervasiveness of chronic pain, the high association of pain and sleep disruption, and the paucity of previous experimental work identifying susceptibility and resilience factors related to chronic pain development. This study is innovative for employing an ecologically valid sleep deprivation paradigm, and utilizing genetically different rat strains to determine the contributions of HPA axis responsivity to persistent mechanical hypersensitivity development and consequent sleep alterations. The successful conduct of the proposed study will provide a platform upon which to build studies focusing on functional outcomes in addition to sleep such as locomotion, mood, and early life pain experiences. The addition of females is a vital next step. PUBLIC HEALTH RELEVACE The prevalence of chronic pain was recently reported to be an alarming 48%, and pain of primarily neuropathic origin was reported to be 8%. Despite the enormous scope of the problem of chronic pain, there is minimal understanding or study of the causes of the transition from acute pain to long-lasting chronic pain. The relevance of the proposed study to human health is the goal to discern what factors (e.g., sleep disruption, biological responses to stress and anxiety) increase one s risk to develop chronic pain.