NOCICEPTIVE MEMORY: MECHANISMS OF HYPEREXCITABILITY

伤害性记忆：过度兴奋的机制

• 批准号: 6639520
• 负责人: EDGAR T. WALTERS
• 金额: $ 33.52万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639520
• 关键词: Aplysia; action potentials; cAMP response element binding protein; calcium flux; cyclic GMP; hyperalgesia; long term memory; nitric oxide; nociceptors; potassium channel; protein kinase; sensory mechanism; transcription factor

Central memory of peripheral injury relies on mechanisms that are likely prototypes of other transcription-dependent forms of long-term memory, and which directly contribute to the clinical problems of persistent hyperalgesia and neuropathic pain. In addition, derangements of these fundamental plasticity mechanisms may contribute to problems of memory and learning in humans. The invertebrate, Aplysia, contains nociceptive sensory neurons with defined roles in defensive behavior and which display long-term hyperexcitability (LTH) of their central as well as peripheral components lasting for days to months after intense noxious stimulation. These sensory neurons are particularly favorable for investigating long-term memory mechanisms because they can be manipulated and tested individually before, during, and after memory induction -- in ways not possible with vertebrate neurons. The proposed studies will test a multiphase hypothesis about the cellular signaling pathways and transcription factors responsible for induction of LTH in these neurons, focusing on the phases that depend upon signals evoked by intense neural activity. A number of specific questions will be systematically addressed. What ionic mechanisms underlie the expression Of LTH? During LTH are there changes in the mRNA levels of any ion channels that have been cloned from Aplysia? How long do different phases of LTH induction last? How do they depend upon NO and cGMP signals? Do NO and PKG act through activation of MAPK? Is prolonged or repeated elevation of intracellular Ca2+ necessary or sufficient to induce LTH? Is prolonged PKA activation important for LTH induction? Is there simultaneous or sequential synergism between cAMP and either Ca2+ or cGMP signals during the induction of LTH? How does the activity of protein kinases potentially important for LTH (e.g. PKG, MAPK IAK-1, PKA, PKC, CaMK, SAPK) change during different phases of the induction and maintenance of LTH? Which transcription factors are required for the rapid induction of LTH? Are any phases of LTH prevented by injection of decoy oligonucleotides encoding response elements such as CRE, SRE and ERE? Can LTH be induced by injection of activated transcription factors? As is evident by the detailed nature of these questions, the proposed experiments directly probe specific pathways that are important for the induction of LTH. Our findings will provide significant insights into fundamental mechanisms important for both memory formation and persistent pain.

外周损伤的中央记忆依赖于可能是其他转录依赖形式的长期记忆的原型的机制，这些机制直接导致持续性痛觉过敏和神经病理性疼痛的临床问题。此外，这些基本可塑性机制的错乱可能会导致人类的记忆和学习问题。无脊椎动物海兔(Aplysia)含有伤害性感觉神经元，在防御行为中具有明确的作用，在强烈的伤害性刺激后，其中枢和外周部分显示出长期的超兴奋性(LTH)，持续数天至数月。这些感觉神经元对研究长期记忆机制特别有利，因为它们可以在记忆诱导之前、期间和之后单独操作和测试--这是脊椎动物神经元不可能做到的。这项拟议的研究将测试一个关于细胞信号通路和转录因子在这些神经元中诱导LTH的多阶段假说，重点放在依赖于强烈神经活动诱发的信号的阶段。将系统地讨论一些具体问题。LTH表达的离子机制是什么？在LTH过程中，从海兔克隆的任何离子通道的mRNA水平是否发生了变化？LTH诱导的不同阶段持续多久？它们如何依赖于NO和cGMP信号？NO和PKG是否通过激活MAPK起作用？细胞内钙离子持续或反复升高是诱发LTH的必要条件还是充分条件？长时间的PKA激活对LTH的诱导重要吗？在LTH的诱导过程中，cAMP与钙离子或cGMP信号之间是否存在同步或顺序的协同作用？在LTH诱导和维持的不同阶段，对LTH具有潜在重要性的蛋白激酶(如PKG、MAPK IAK-1、PKA、PKC、CaMK、SAPK)的活性是如何变化的？LTH的快速诱导需要哪些转录因子？注射编码CRE、SRE和ERE等反应元件的诱骗寡核苷酸是否可以预防LTH的任何阶段？注射激活的转录因子能诱导LTH吗？从这些问题的详细性质可以明显看出，拟议的实验直接探索对LTH的诱导至关重要的特定途径。我们的发现将对记忆形成和持续性疼痛的基本机制提供重要的见解。