MECHANISMS OF HYPERALGESIA IN THE SPINAL DORSAL HORN

脊髓背角痛觉过敏的机制

• 批准号: 6729156
• 负责人: VJEKOSLAV MILETIC
• 金额: $ 21.6万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2006-01-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729156
• 关键词: cAMP response element binding protein; calcineurin; dorsal horn; evoked potentials; hyperalgesia; immunocytochemistry; laboratory rat; long term potentiation; membrane potentials; neural inhibition; neural plasticity; neuropharmacology; neurophysiology; phosphorylation; protein kinase A; sciatic nerve; western blottings

DESCRIPTION: (Adapted from the Investigator's Abstract) The overall goal of this proposal remains to investigate how sciatic ligation produces plastic changes in dorsal horn neuronal excitability to ultimately contribute to the development of neuropathic pain. In the past funding period we sought to establish whether electrophysiological correlates of synaptic plasticity could be recorded in the spinal dorsal horn in vivo. We also wanted to determine whether these phenomena were a normal feature of spinal nociceptive processing, or were only elicited after injury. We established that in control animals, a given tetanic protocol favored post-tetanic depression, while in ligated animals the same tetanic protocol favored potentiation. We assume that both intracellular and extraneous (synaptic) influence combine to produce a given post-tetanic response, and that a balance between excitatory and inhibitory processes determines whether potentiation or depression will ensue. In this competitive renewal we wish to: (1) determine which processes contribute to the balance between potentiation and depression, and (2) establish how sciatic ligation affects these processes. Overall, we hypothesize that a critical change in the action of one or more of these processes leads to the differential pattern of post-tetanic responses between control and ligated rats. In Specific Aim 1 we will continue to record sciatic-evoked dorsal horn A beta and A delta fiber field potentials. We will employ selected agonists, antagonists, activators or inhibitors to test two specific hypotheses as we ask: (1) Does GABAA receptor-mediated inhibition contribute to the depression in control rats, and does the loss of this inhibition contribute to the potentiation in ligated animals? (2) Does activation of calcineurin contribute to the depression in control animals, and is the loss of this action reflected in the ligated response? Similarly, does protein kinase A (PKA) activation contribute to the initial potentiation in both groups of animals, or is the kinase activated only in ligated animals? Additional preliminary data suggest that metaplasticity may play a critical role in spinal nociception. In this Aim we will also examine the roles of GABA, PKA and calcineurin in spinal metaplasticity. In Specific Aim 2 we will focus on the cAMP responsive element binding protein (CREB). Recent evidence suggests that phosphorylation of CREB plays a critical role in long-lasting synaptic plasticity. We will employ immunocytochemical and Wesern immunolot procedures to test two specific hypotheses as we ask: (1) When does pCREB (pCREB) first appear in ligated rats, and does its appearance and disappearance correlate with thermal hyperalgesia and synaptic plasticity? and (2 Do changes in immunoreactive PKA and calcineurin content in the spinal dorsal horn parallel the onset and disappearance of thermal hyperalgesia and spinal synaptic plasticity?

描述：（根据调查员的摘要进行了改编） 该提案的总体目标仍然是调查坐骨神经结扎的方式 产生背角神经元兴奋性的塑性变化，以最终 有助于神经性疼痛的发展。在过去的资金期间 我们试图确定突触的电生理学是否相关 可塑性可以记录在体内的脊柱背角。我们也想要 确定这些现象是否是脊柱的正常特征 伤害性处理，或仅在受伤后引起。我们确定了这一点 在对照动物中，给定的四烷式方案有利于四局抑郁症， 在连接的动物中，相同的四烷式方案有利于增强。我们 假设细胞内和外部（突触）影响合并到 产生给定的后反应，并在兴奋之间达到平衡 抑制过程决定了增强或抑郁症是否会 随后。在这种竞争性更新中，我们希望：（1）确定哪些过程 有助于增强和抑郁之间的平衡，（2） 确定坐骨神经结扎如何影响这些过程。总体而言，我们假设 这些过程中一个或多个过程的行动的关键变化导致 控制和连接之间的触发后反应的差异模式 老鼠。在特定目标1中，我们将继续记录坐骨神见的背喇叭 Beta和Delta纤维场电位。我们将采用选定的激动剂， 我们 问：（1）GABAA受体介导的抑制是否有助于抑郁症 在对照大鼠中，这种抑制作用的丧失有助于 结扎动物的增强？ （2）钙调神经酶的激活有助于 对控制动物的抑郁症，这是反映的动作的丧失 在连接的响应中？同样，蛋白激酶A（PKA）激活 有助于两组动物的初始增强，或者是 激酶仅在结扎的动物中激活？其他初步数据建议 这种塑性性可能在脊柱伤害受伤中起关键作用。在这个目标中 我们还将检查GABA，PKA和钙调蛋白在脊柱中的作用 化学性。在特定目标2中，我们将重点放在营地响应元素上 结合蛋白（CREB）。最近的证据表明CREB的磷酸化 在持久的突触可塑性中起着至关重要的作用。我们将雇用 免疫细胞化学和WESERN免疫程序测试两个特定的程序 当我们提出的假设：（1）何时pcreb（pcreb）首先出现在结扎的大鼠中， 并且其外观和消失与热痛觉过敏相关 和突触可塑性？ （2做免疫反应性PKA和 脊柱背角中的钙调神经素含量平行于发作和发作 热痛觉过敏和脊柱突触可塑性的消失？