IMMUNOREACTIVE TACHYKININS IN SPINAL CORD RELEASATES

脊髓释放物中的免疫反应性速激肽

• 批准号: 6270300
• 负责人: Allan I. Basbaum
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6270300
• 关键词: analgesia; analgesics; capsaicin; dorsal horn; endogenous opioid; excitatory aminoacid; glutamates; histology; hyperalgesia; immunocytochemistry; immunologic assay /test; in situ hybridization; laboratory rat; microdialysis; neural plasticity; neuroanatomy; neurochemistry; neuropeptide receptor; neurotransmitter transport; opioid receptor; pain; receptor expression; spinal cord injury; substance P; tachykinin

There is considerable evidence that noxious stimulation produces N-methyl- D-aspartate (NMDA)-mediated long-term changes in the physiology and chemistry of dorsal horn neurons. Our laboratory has provided new evidence that links the neurotransmitter Substance P(SP) to these changes. We have demonstrated rapid internalization of the substance P receptor (SPR) in subpopulations of spinal cord neurons in response to stimulation with SP. There is also a dramatic and reversible structural reorganization of the dendrites of neurons that express the SPR. The dendrites become highly varicose and the diameter of the dendrites between varicosities is significantly reduced, compared to normal. We have also demonstrated that intrathecal injection of NMDA or noxious stimulation of the hindpaw evokes these changes. This suggests that these changes are a normal response to SP-mediated inputs. Our proposed studies will further characterize the neurons that undergo these changes and will address the opioid regulation of these changes. In related study we will use antisera directed against the recently cloned opioid receptors to determine the relationship of neurons that express the SPR with those that express the opioid receptors. We hypothesize that the structural changes of neurons that express the SPR constitute a significant component of the noxious stimulus-evoked short and long-term changes in spinal cord neurons, and suggest that NMDA-mediated hyperalgesic states result at least in part from release of SP from primary afferent fibers. We will test these hypotheses using anatomical, neurochemical, physiological and pharmacological approaches. We will also test the hypothesis that changes in the process of SPR internalization contribute to the differences that characterize nociceptive and neuropathic pain models, which are respectively associated with chronic up and downregulation of SP levels in the dorsal horn. Taken together these studies will provide important new information on the pathophysiology and the clinical consequences of injury-evoked long-term changes in the spinal cord dorsal horn.

有相当多的证据表明，伤害性刺激产生N-甲基-N D-天冬氨酸（NMDA）介导的长期生理变化， 背角神经元化学 我们的实验室提供了 神经递质P物质（SP）与这些变化有关的证据。 我们已经证明了P物质受体的快速内化 (SPR)脊髓神经元亚群对刺激的反应 与SP。还有一个戏剧性的和可逆的结构 表达SPR的神经元树突的重组。 的 树突变得高度曲张， 与正常相比，静脉曲张显著减少。 我们还 表明鞘内注射NMDA或伤害性刺激 后爪唤起了这些变化。 这表明，这些变化是一个 对SP介导的输入的正常反应。 我们建议的研究将进一步 描述经历这些变化的神经元，并将解决 阿片类药物调节这些变化。 在相关研究中，我们将使用抗血清 针对最近克隆的阿片受体，以确定 表达SPR的神经元与表达 阿片受体 我们假设神经元的结构变化 表达SPR的蛋白质构成了有毒物质的重要组成部分， 脊髓神经元中刺激诱发的短期和长期变化，以及 表明NMDA介导痛觉过敏状态至少部分导致 从初级传入纤维释放SP。 我们将测试这些 利用解剖学、神经化学、生理学和 药理学方法。 我们还将检验假设， 在SPR内化的过程中， 描述伤害性和神经性疼痛模型， 分别与慢性上调和下调SP水平有关， 背角 这些研究将提供重要的新信息。 有关病理生理学和临床后果的信息 损伤诱发的脊髓背角长期变化。