Cellular Mechanisms of Hyperalgesia and Opioid Tolerance

描述：(申请人提供) 在NIH资助的过去五年中，我们在以下方面取得了重大进展 完成原研究项目提出的具体目标。这个 工作进度报告总结的研究结果显示，有三条主要路线： 脊髓N-甲基-D-天冬氨酸与阿片类药物的相互作用 与痛觉过敏和阿片类药物耐受有关的受体系统。此外， 这些发现揭示了潜在的不可逆转的退行性神经元变化。 与痛觉过敏和阿片类药物耐受有关。因为NMDA和阿片类药物 受体代表伤害性感受相关的两个重要系统 神经可塑性和抗伤害感受，这项相互竞争的拨款续期的目标 继续在上一个供资期间开展卓有成效的工作， 为了进一步研究神经和分子机制之间的相互作用 这两个受体系统。多学科方法，包括行为学、 将使用药理学和免疫细胞化学的方法来完成 三个具体目标：(1)研究NMDA和p-阿片类药物的共定位 脊髓神经元中的受体并确定其局部分布 在有和没有痛觉过敏或类阿片类药物的大鼠中这种共定位的研究 耐受性；(2)观察大鼠脑内神经元退行性改变的性质。 脊髓与痛觉过敏和β-阿片类药物耐受的关系及探讨 阿片类药物治疗的时程和量效关系 退行性神经元改变的发生；以及(3)确定 退行性变患者NMDA受体激活及相关细胞内变化 与β-阿片耐受相关的神经元变化。这项拟议的工作是 对先前研究的合乎逻辑的延续，这将提供新颖和 关于NMDA之间细胞和细胞内相互作用的重要信息 和β-阿片受体，以及这些相互作用在痛觉过敏和 β-阿片耐受性。因此，这项工作的结果可能有助于改善 阿片类止痛药在治疗癌症和慢性疼痛中的临床应用 综合症。重要的是，阿片类药物诱导的退行性神经元的研究 变化及其与病理生理疼痛状态的关系可能提供 对痛觉过敏和阿片类药物耐受的神经生物学的洞察， 可能会导致更多的临床应用。

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.