NOCICEPTIVE MEMORY: MECHANISMS OF HYPEREXCITABILITY

伤害性记忆：过度兴奋的机制

• 批准号: 6393858
• 负责人: EDGAR T. WALTERS
• 金额: $ 33.32万
• 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/6393858
• 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.

外周损伤的中枢记忆所依赖的机制可能是其他转录依赖性长期记忆形式的原型，并且直接导致持续性痛觉过敏和神经性疼痛的临床问题。 此外，这些基本可塑性机制的紊乱可能会导致人类的记忆和学习问题。 无脊椎动物海兔含有伤害性感觉神经元，在防御行为中具有明确的作用，并且在强烈的伤害性刺激后，其中枢和外周成分表现出长期过度兴奋（LTH），持续数天至数月。 这些感觉神经元特别有利于研究长期记忆机制，因为它们可以在记忆诱导之前、期间和之后单独进行操作和测试——这是脊椎动物神经元不可能实现的。拟议的研究将测试关于负责在这些神经元中诱导 LTH 的细胞信号通路和转录因子的多相假设，重点关注依赖于强烈神经活动诱发的信号的阶段。 将系统地解决一些具体问题。 LTH 表达的离子机制是什么？ 在 LTH 期间，从海兔克隆的任何离子通道的 mRNA 水平是否会发生变化？ LTH 诱导的不同阶段持续多长时间？ 它们如何依赖于 NO 和 cGMP 信号？ NO 和 PKG 是否通过激活 MAPK 发挥作用？ 细胞内 Ca2+ 的长期或反复升高是否有必要或足以诱导 LTH？ 延长 PKA 激活对于 LTH 诱导是否重要？ 在 LTH 诱导过程中，cAMP 与 Ca2+ 或 cGMP 信号之间是否存在同时或顺序协同作用？在 LTH 诱导和维持的不同阶段，对 LTH 潜在重要的蛋白激酶（例如 PKG、MAPK IAK-1、PKA、PKC、CaMK、SAPK）活性如何变化？快速诱导 LTH 需要哪些转录因子？ LTH 的任何阶段是否可以通过注射编码 CRE、SRE 和 ERE 等反应元件的诱饵寡核苷酸来预防？ 注射活化的转录因子可以诱导 LTH 吗？ 从这些问题的详细性质可以明显看出，所提出的实验直接探测对于诱导 LTH 很重要的特定途径。 我们的研究结果将为记忆形成和持续性疼痛的重要基本机制提供重要见解。