Persistent Mechanical Hypersensitivity in Rats: Biobehavioral Effects

描述（由申请人提供）：令人震惊的是，26%的美国人报告在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向持续性疼痛综合征转变的因果途径的理解或研究很少。持续性疼痛的临床模型表明急性疼痛的经历和慢性疼痛发展的过程中存在很大的变异性，而临床前模型表明急性疼痛的经历或持续性疼痛的发展存在很小的变异性。这项新的合作努力的长期目标是系统地利用已建立的临床前模型，该模型提供了研究对持续性疼痛发展的易感性和恢复力的机会。我们的总体假设是，生物行为因素，如睡眠中断和改变下丘脑-垂体-肾上腺（HPA）轴的压力反应都有助于和结果的发展持续性疼痛的条件。我们建议利用坐骨神经炎性神经炎（SIN）模型，有利于分离手术损伤疼痛的启动，和酵母多糖剂量的可控性和可变性的疼痛引发剂，以解决两个具体的目标在雄性大鼠：（1）确定睡眠中断的影响，持续炎症诱导的机械超敏反应的发展。将比较保持不受干扰的大鼠与每天从第一次SIN导管酵母聚糖输注前一天到第10次和最后一次每天酵母聚糖输注的光照后前6小时内睡眠尝试因温和处理而中断的大鼠之间持续炎症诱导的机械性超敏反应的发生率和严重程度。(2)确定HPA轴反应性对持续性炎症诱导的机械超敏反应的影响及其对睡眠-觉醒行为的影响。将比较近交系HPA轴低反应性刘易斯和HPA轴高反应性Fischer 344大鼠以及远系Sprague道利大鼠炎症诱导的持续性机械超敏反应的发生率和严重程度及其对睡眠-觉醒行为的影响。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相关性，以及缺乏以前的实验工作，确定与慢性疼痛发展相关的易感性和弹性因素。这项研究是创新的采用生态有效的睡眠剥夺范式，并利用遗传上不同的大鼠品系，以确定HPA轴反应的贡献，持续机械超敏反应的发展和随之而来的睡眠改变。拟议研究的成功进行将提供一个平台，在此基础上建立研究，重点关注除睡眠外的功能结果，如运动，情绪和早期生活疼痛体验。增加女性是至关重要的下一步。 公共卫生相关性最近报告慢性疼痛的患病率达到惊人的48%，据报告主要神经性疼痛为8%。尽管慢性疼痛问题的范围很广，但对从急性疼痛转变为长期慢性疼痛的原因的了解或研究很少。拟议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.