Persistent Mechanical Hypersensitivity in Rats: Biobehavioral Effects

描述（由申请人提供）：令人震惊的26%的美国人报告疼痛在上个月持续超过一天，其中42%的人表示他们的疼痛持续超过一年。尽管慢性疼痛问题的范围很广，但对从急性疼痛状况到持续疼痛综合征过渡的因果途径的理解或研究却很少。持续疼痛的临床模型表明急性疼痛体验和慢性疼痛发展过程有很大的可变性，而临床前模型显示急性疼痛体验或持续疼痛发展的可变性很小。这项新的合作努力的长期目标是系统地利用一个已建立的临床前模型，为研究对持续疼痛发展的易感性和恢复力提供机会。我们的首要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，都有助于持续疼痛状况的发展和结果。我们建议利用坐骨炎症性神经炎（SIN）模型，将手术损伤与疼痛起始分离开来，并利用酶多糖剂量作为疼痛起始剂的可控性和可变性，来解决雄性大鼠的两个具体目标：(1)确定睡眠中断对持续炎症诱导的机械超敏反应发展的影响。将比较持续炎症引起的机械超敏反应的发生和严重程度，分别是未受干扰的大鼠和每天轻起后6小时内被温和处理干扰睡眠的大鼠，从第一次注射SIN导管酶生蛋白的前一天开始，到第10次和最后一次注射酶生蛋白。(2)探讨HPA轴反应性对持续性炎症性机械超敏反应的影响及其对睡眠-觉醒行为的影响。比较近交系HPA轴低反应性Lewis大鼠和HPA轴高反应性Fischer 344大鼠以及远交系Sprague Dawley大鼠炎症性持续性机械超敏反应的发生、严重程度及其对睡眠-觉醒行为的影响。该研究的意义在于慢性疼痛的普遍性，疼痛与睡眠中断的高度关联，以及先前缺乏确定慢性疼痛发展相关的易感性和弹性因素的实验工作。这项研究的创新之处在于采用了生态有效的睡眠剥夺模式，并利用基因不同的大鼠品系来确定HPA轴对持续机械超敏反应发展和随后的睡眠改变的贡献。该研究的成功实施将提供一个平台，在此基础上建立除睡眠之外的功能结果研究，如运动、情绪和早期生活疼痛经历。雌性的加入是至关重要的下一步。公共卫生相关性：最近有报道称慢性疼痛的患病率达到了惊人的48%，而神经性疼痛的发生率为8%。尽管慢性疼痛的问题范围很大，但对从急性疼痛到长期慢性疼痛过渡的原因的理解或研究却很少。拟议的研究与人类健康的相关性是为了辨别哪些因素（例如，睡眠中断，对压力和焦虑的生物反应）增加了一个人患慢性疼痛的风险。

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.