Cellular Mechanisms of Hyperalgesia and Opioid Tolerance

描述：（申请人提供） 在过去五年的NIH资助中，我们在以下方面取得了重大进展 实现了原研究项目中提出的具体目标。的 进展报告中总结的调查结果表明， 脊髓N-甲基-D-天冬氨酸（NMDA）与阿片类药物的相互作用 受体系统与痛觉过敏和阿片耐受性的关系。此外，委员会认为， 这些发现揭示了潜在的不可逆的退行性神经元变化 与痛觉过敏和阿片类药物耐受有关。由于NMDA和阿片类药物 受体代表伤害感受相关的两个重要系统 神经可塑性和抗伤害感受，这一竞争性赠款更新的目标， 是继续在上一个供资期内开展的卓有成效的工作， 进一步研究神经和分子机制的相互作用， 这两个受体系统。多学科方法，包括行为、 药理学和免疫细胞化学方法将用于完成 三个具体目标：（1）检查NMDA和p-阿片样物质的共定位 受体的脊髓神经元，并确定地形分布 在有和没有痛觉过敏或μ-阿片样物质的大鼠中， 耐受性;（2）检查神经元退行性变化的性质， 脊髓与痛觉过敏和p-阿片耐受相关，并探讨 阿片类药物治疗的时程和量效关系 发生退行性神经元变化;（3）确定 退行性变中NMDA受体活化及其相关的细胞内变化 与p-阿片耐受相关的神经元变化。这项工作是一个 逻辑上的延续以前的研究，这将提供新的和 NMDA与细胞内和细胞内相互作用的重要信息 和p-阿片受体，以及这种相互作用在痛觉过敏和 对阿片类药物的耐受性因此，这项工作的结果可能有助于改善 阿片类镇痛药治疗癌症和慢性疼痛的临床应用 综合征重要的是，研究阿片类药物诱导的退行性神经元 变化及其与病理生理疼痛状态的关系可能提供 深入了解痛觉过敏和阿片耐受的神经生物学， 可能导致额外的临床应用。

DESCRIPTION: (provided by applicant) During the last five years of NIH funding, we have made significant progress in accomplishing the specific aims outlined in the original research project. The findings summarized in the Progress Report indicate three major lines of interactions between the spinal cord N-methyl-D-aspartate (NMDA) and opioid receptor systems in relation to hyperalgesia and opioid tolerance. Moreover, these findings reveal potentially irreversible degenerative neuronal changes associated with hyperalgesia and opioid tolerance. Since NMDA and opioid receptors represent two important systems in nociception-related neuroplasticity and antinociception, the goal of this competing grant renewal is to continue the fruitful work carried out over the last funding period and to further investigate neural and molecular mechanisms of interactions between these two receptor systems. Multidisciplinary approaches including behavioral, pharmacological, and immunocytochemical methods will be used to accomplish three specific aims: (1) To examine co-localization of NMDA and p-opioid receptors in spinal cord neurons and to determine the topographic distribution of such co-localization in rats with and without hyperalgesia or mu-opioid tolerance; (2) To examine the nature of degenerative neuronal changes in the spinal cord associated with hyperalgesia and p-opioid tolerance and to explore the time course and dose-response relationship of opioid treatment with the occurrence of degenerative neuronal changes; and (3) To determine the role of NMDA receptor activation and related intracellular changes in degenerative neuronal changes associated with p-opioid tolerance. This proposed work is a logical continuation of previous studies, which will provide novel and important information on cellular and intracellular interactions between NMDA and p-opioid receptors and on the role of such interactions in hyperalgesia and p-opioid tolerance. Thus, the results from this work may help improve the clinical utility of opioid analgesics in treating cancer and chronic pain syndromes. Importantly, investigations of opioid-induced degenerative neuronal changes and their relation to pathophysiological pain states may provide insights into the neurobiology of both hyperalgesia and opioid tolerance, which could result in additional clinical applications.