NOCICEPTIVE MEMORY: MECHANISMS OF HYPEREXCITABILITY

伤害性记忆：过度兴奋的机制

• 批准号: 6193801
• 负责人: EDGAR T. WALTERS
• 金额: $ 34.31万
• 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/6193801
• 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.

外围损伤的中央记忆取决于可能是其他转录依赖性长期记忆形式的原型的机制，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毁灭可能导致人类记忆和学习问题。 无脊椎动物Aplysia包含具有明确作用的伤害感官感觉神经元，它们在其中心表现出长期过度抗性性（LTH）以及在强烈有害刺激后数天至几个月持续的外围成分。 这些感觉神经元特别有利于研究长期记忆机制，因为它们在记忆诱导之前，之中和之后可以单独测试和测试 - 脊椎动物神经元无法以可能的方式进行。拟议的研究将检验有关这些神经元中LTH诱导的细胞信号传导途径和转录因子的多相假设，重点是依赖于强烈的神经活动引起的信号的阶段。 许多具体问题将系统地解决。哪些离子机制是LTH表达的基础？ 在lth期间，从垂直溶质克隆的任何离子通道的mRNA水平会发生变化吗？ LTH归纳的不同阶段持续多长时间？ 它们如何依赖于NO和CGMP信号？不是通过激活MAPK来起作用吗？ 细胞内Ca2+的延长或反复升高是否需要或足以诱导LTH？ 长时间的PKA激活对LTH诱导重要吗？ 在LTH诱导期间，CAMP和CA2+或CGMP信号之间是否同时或顺序的协同作用？在LTH的不同阶段和LTH的不同阶段，蛋白激酶的活性对LTH（例如PKG，MAPK IAK-1，PKA，PKC，CAMK，SAPK）有可能重要吗？快速诱导LTH需要哪些转录因子？ 注射了编码响应元件（例如CRE，SRE和ERE）的诱饵寡核苷酸阻止LTH的任何阶段？ 可以通过注射激活的转录因子来诱导LTH吗？ 正如这些问题的详细性质所看出的那样，提出的实验直接探测了对LTH诱导至关重要的特定途径。 我们的发现将为对记忆形成和持续性疼痛重要的基本机制提供重大见解。