MECHANISMS OF PAIN AND ANALGESIA

大量的慢性疼痛患者构成了一个重大的人类悲剧，一个重大的经济负担，反映了我们对疼痛机制的理解不足。本项目研究疼痛和阿片类镇痛的神经生物学。该计划的重点是促进互动，积极合作和临床意义的研究。这一目标将通过每两周一次的研究会议和分享设备和技术、抗体、基因操纵小鼠来实现。解剖核心将通过提供共聚焦和电子显微镜支持服务于五个项目中的四个。结合解剖学、电生理学和药理学技术，Basbaum博士将研究一种独特的非肽能性初级传入伤害感受器，这些感受器终止于内胶状物质。他将利用这一发现，即血清素在5HT3受体选择性作用下激活这些传入事件。菲尔兹博士将阐明介导疼痛的情感动机方面的神经通路。他将使用福尔马林作为有害刺激，并将条件性地方厌恶作为行为测试。Drs。菲尔兹和巴斯鲍姆将合作研究含p物质和非肽能初级传入对厌恶的贡献。菲尔兹将研究脑脊髓束、脊髓丘脑束、前扣带、体感觉和非颗粒状岛皮质在厌恶中的作用。他将与Ralston博士合作从解剖学上定义从丘脑内侧到前扣带皮层的伤害性传递。Ralston博士将继续研究外周神经损伤后中央体感通路的超微结构变化。Levine将使用行为学方法，以及体内原发性传入神经和离体背根神经节记录，研究啮齿动物实验性糖尿病神经病中疼痛和痛觉过敏的细胞机制。Drs。Ralston和Levine将合作进行末梢神经和背角重组的超微结构研究。在正常的人类志愿者和病人中。Rowbotham和Fields将研究与阿片类镇痛相关的两个重要临床问题。首先，是否存在阿片类不敏感疼痛？第二，慢性疼痛患者长期使用阿片类药物是否会产生镇痛耐受性？这些问题将使用一种新的方法（热后辣椒素）来研究产生阿片类药物反应性疼痛和皮肤痛觉过敏。阿片类药物的镇痛作用可以在同一患者的临床和实验疼痛中进行研究。

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.