MECHANISMS OF PAIN AND ANALGESIA

大量慢性疼痛患者构成了重大的人类悲剧，是重大的经济负担，反映了我们对疼痛机制的了解不足。该计划项目涉及疼痛和阿片类止痛的神经生物学。该计划的重点是促进互动、积极合作和具有临床意义的研究。这一目标将通过每两周一次的研究会议以及分享设备和技术、抗体、基因操纵的小鼠来实现。解剖核心将通过提供共焦和电子显微镜支持来服务于五个项目中的四个。巴斯鲍姆博士将结合解剖学、电生理学和药理学技术，研究终止于内侧胶状质的一组独特的非肽能初级传入伤害性感受器。他将利用这一发现，即作用于5HT3受体选择性的5-羟色胺可以激活这些传入神经。菲尔兹博士将阐明调节疼痛情绪-动机方面的神经通路。他将使用福尔马林作为有害刺激，并将条件性场所厌恶作为行为测试。菲尔兹博士和巴斯鲍姆博士将合作研究P物质和非肽能初级传入神经对厌恶感的贡献。菲尔德将研究脊髓中脑和脊丘脑束以及前扣带回、躯体感觉和颗粒紊乱的岛叶皮质在厌恶中所起的作用。他将与拉尔斯顿博士合作，从解剖学上定义从内侧丘脑到前扣带回皮质的伤害性传递。拉尔斯顿博士将继续研究周围神经损伤后中枢躯体感觉通路的超微结构变化。Levine将利用行为学方法以及体内初级传入和体外背根神经节记录，研究啮齿动物实验性糖尿病神经病变中疼痛和痛敏的细胞机制。Ralston博士和Levine博士将在这种神经病变的周围神经和背角重组的超微结构研究方面进行合作。在正常人志愿者和患者中，Rowbotham和Fields博士将研究与阿片类药物止痛相关的两个重要临床问题。首先，有阿片类药物不敏感的疼痛吗？第二，慢性疼痛患者是否会随着阿片类药物的长期使用而产生止痛耐受？这些问题将使用一种新的方法(加热后辣椒素)来研究，以产生阿片类反应性疼痛和皮肤痛敏。然后在同一患者身上研究阿片类药物对临床和实验疼痛的止痛效果。

The large number of patients with chronic pain constitutes a major human tragedy, a significant economic burden and is a reflection of our inadequate understanding of pain mechanisms. This program project addresses the neurobiology of pain and opioid analgesia. The emphasis of the program is to promote interaction, active collaboration and clinically significant research. This goal will be achieved through biweekly research conferences and sharing of equipment and techniques, antibodies, genetically manipulated mice. The anatomical core will serve four of the five projects by providing confocal and electron microscopic support. Using a combination of anatomical, electrophysiological and pharmacological techniques, Dr. Basbaum will investigate a unique population of non-peptidergic primary afferent nociceptors that terminate in the inner substantia gelatinosa. He will exploit this finding that serotonin acting at the 5HT3 receptor selectivity activates these afferents. Dr. Fields will elucidate the neural pathways that mediate the affective- motivational aspect of pain. He will employ formalin as the noxious stimulus and conditioned place aversion as the behavioral test. Drs. Fields and Basbaum will collaborate to investigate the contributions of both substance P-containing and non-peptidergic primary afferents to aversiveness. Fields will study the role in aversion of the spinomesencephalic and spinothalamic tracts and the anterior cingulate, somatosensory, and dysgranular insular corteces. He will collaborate with Dr. Ralston to anatomically define the nociceptive relay from medial thalamus to anterior cingulate cortex. Dr. Ralston will continue his studies of ultrastructural changes in central somatosensory pathways following peripheral nerve injury. Levine, using behavioral methods and both in vivo primary afferent and in vitro dorsal root ganglion recordings, will study the cellular mechanisms of pain and hyperalgesia in rodent experimental diabetic neuropathy. Drs. Ralston and Levine will collaborate on ultrastructural studies of peripheral nerve and of dorsal horn reorganization in this neuropathy. In normal human volunteers and patients Drs. Rowbotham and Fields will investigate two important clinical issues related to opioid analgesia. First, are there opioid insensitive pains? Second, does analgesic tolerance develop with prolonged use of opioids in patients with chronic pain? These issues will be studied using a new method (heat followed by capsaicin) to produce opioid responsive pain and cutaneous hyperalgesia. The analgesic effect of opioidscan then be studied in the same patient for both clinical and experimental pain.