模型猴神经痛行为学与脑脊液神经化学的关联性和疼痛的生物学影响

The main methodology used in pain medicine research is behavioral study in animal models. This application is submitted based on the following reasons that, 1) due to ethics and subjectivity limitations, human being can't be used as pain research models, 2) in vitro studies and lower specie animal models can't reflect the effects of pain to the suffering individuals and the groups they live in, 3) the current pain testing method, which tests hyperalgesia and allodynia instead of spontaneous pain, can't detect the real status of clinical pain, 4) clinically, there are some patients who are unable to describe the pain they are suffering, and it is necessary to discover objective indicators to diagnose their pain status, and 5) nonhuman primate cynomolgus monkeys have larger body and longer life span than rodents, and similar to human being in terms of anatomy, physiology, social behavior and so on. In this project we will make trigeminal neuralgia model in cynomolgus monkeys using mental nerve chronic constrictive injuries (CCI), and study 1) the occurrence and development of neuropathic pain in individual, 2) the correlation of neuropathic pain behavior and cerebrospinal fluid neurochemistry, and 3) the long-term biological effects of pain on the suffering individuals, their offsprings, and the groups they live in. Methodologies of pain behavior, cerebrospinal fluid neurochemistry, population biology and statistics will be used. By this project, we are expecting to 1) develop a primate animal model with pain status that appear in human neuropathic pain patients, 2) clarify the difference between anterior and posterior pain modelling in both spontaneous pain behavior and the cerebralspinal fluid neurochemistry, find a possible correlation between them, and design pain diagnostic chips based on the correlation, and 3) show the biological effect of pain to the suffering individuals, their offsprings, and the groups they live in. The results will contribute to the research, understanding, prognosis and treatment of pain.

疼痛医学以模型动物行为学研究为主要手段。基于原因，1）限于伦理和主观性，人类不宜作疼痛研究模型，2）离体研究和低等动物模型不能反映疼痛对个体和群体的影响，3）现有疼痛研究以测定痛觉过敏代替测定自发痛，不能反映真实的疼痛状态，4）临床上，部分患者不能表述疼痛，需要客观指标予以诊断，5）食蟹猴在生理学、社会行为学等方面接近人类，项目将在食蟹猴施行慢性颏神经挤压性损伤手术，制备三叉神经痛模型，综合疼痛行为学、脑脊液神经化学、生物学和统计学方法，研究：1）神经痛在个体的发生发展，2）神经痛行为与脑脊液神经化学的相关性，3）疼痛对个体、后代和群体的生物学影响。项目预期将：1)开发出接近人类神经痛状态的动物模型，2) 阐明自发痛行为和与之关联的神经化学变化规律，基于此设计疼痛诊断芯片，3）展现疼痛对个体和群体的生物学影响。项目结果将有助于疼痛的研究、理解、预后和治疗。

项目成功开发了慢性神经性疼痛猴模型和2型糖尿病猴模型，确定了两者的制备方法。其中，神经痛模型需手术制备，而2型糖尿病模型依赖光污染诱导。.急性疼痛慢性化、外周疼痛中枢化、慢性疼痛的生物学效应等是项目的前期研究内容。项目以食蟹猴为研究对象，成功制备了“三叉神经痛”和 “坐骨神经痛”疾病猴模型。研究发现，小范围的慢性疼痛，如颏神经结扎诱导的三叉神经痛，只在造模后1-4周的时间段内扰乱血糖水平，可能不会诱发2型糖尿病。大范围的慢性神经病变，如坐骨神经结扎诱导的神经痛，能够导致造模后1-24周时间段内的血糖代谢紊乱，在部分模型猴可能最终导致2型糖尿病。.慢性疼痛和夜间睡眠环境光污染与糖代谢的相关性是项目后半程的主要研究内容。项目以食蟹猴为模型动物，研究了慢性疼痛和夜间睡眠环境光污染对糖代谢的负面效应，及消除诱因对疼痛和2型糖尿病的缓解作用。研究发现，在原发性2型糖尿病猴，光污染导致部分模型猴死亡；在血糖代谢正常的实验猴，慢性疼痛与夜间睡眠环境光污染一样，都能导致生物节律紊乱，是糖耐量受损和2型糖尿病的两个重要诱因；在诱导造模的1-7个月时间段内，2型糖尿病发病率逐渐增高，且与污染的光强正相关；而消除神经痛的诱因或去除光污染源1-3个月内，部分实验猴糖代谢紊乱能够在一定程度上缓解，血糖水平逐渐恢复正常；在部分已经诱导成功的2型糖尿病模型，在去除诱导条件后4－8周，甚至会自动恢复糖代谢机能，但多数模型猴维持代谢紊乱状态。.积极治疗疼痛和防止夜间睡眠环境光污染，将能够在正常糖代谢人群降低糖耐量受损和2型糖尿病的发病率、降低2型糖尿病死亡率；在城市规划中应考虑降低光污染和预防疾病的相关性。