NOCICEPTIVE MEMORY: MECHANISMS OF HYPEREXCITABILITY

外周损伤的中枢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，并且其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记忆和学习的问题。 无脊椎动物，Aaplasia，包含伤害性感觉神经元，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持续数天至数月的长期过度兴奋性（LTH）。 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，期间和之后单独操作和测试-脊椎动物神经元不可能的方式。拟议的研究将测试一个多相假说的细胞信号通路和转录因子负责诱导LTH在这些神经元，集中在依赖于强烈的神经活动引起的信号的阶段。 将系统地处理一些具体问题。LTH表达的离子机制是什么？ 在LTH过程中，是否有任何离子通道的mRNA水平的变化，已克隆从拟南芥？ LTH诱导的不同阶段持续多长时间？ 它们如何依赖NO和cGMP信号？NO和PKG是否通过激活MAPK起作用？ 细胞内Ca 2+的长期或反复升高是否是诱导LTH所必需或充分的？ PKA激活延长对LTH诱导重要吗？ 在LTH的诱导过程中，cAMP与Ca ~（2+）或cGMP信号之间是否存在同时或顺序的协同作用？在LTH诱导和维持的不同阶段，对LTH可能重要的蛋白激酶（例如PKG、MAPK IAK-1、PKA、PKC、CaMK、SAPK）的活性如何变化？LTH的快速诱导需要哪些转录因子？ 是否通过注射编码应答元件（如CRE、SRE和ERE）的诱饵寡核苷酸阻止了LTH的任何阶段？ 注射激活的转录因子能诱导LTH吗？ 正如这些问题的详细性质所表明的那样，所提出的实验直接探测对诱导LTH很重要的特定途径。 我们的发现将为记忆形成和持续性疼痛的基本机制提供重要的见解。

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.