Endogenous Agmatine in Glutamatergic Pain Processing

谷氨酸疼痛处理中的内源胍丁胺

• 批准号: 6888156
• 负责人: Carolyn A Fairbanks
• 金额: $ 14.19万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6888156
• 关键词: electrophysiology; glutamate receptor; guanidines; hyperalgesia; laboratory rat; neural information processing; neural initiation; neurophysiology; nucleic acid purification; pain; spinal cord injury; spinal ganglion; voltage /patch clamp

DESCRIPTION: (Provided by Applicant) This application is for a Mentored Research Scientist Development Award (K01). Recently, agmatine (decarboxylated arginine) has been isolated from mammalian brain and spinal cord. Agmatine both antagonizes the NMDA receptor and inhibits nitric oxide synthase (NOS). Because glutamate is thought to drive synaptic plasticity by activating both NMDA receptors and NOS in series, it is conceivable that agmatine participates in control of synaptic plasticity and related behavioral phenomena (e.g. learning and memory, opioid tolerance, chronic pain) as a neuromodulator of glutamate. Exogenously administered agmatine has been shown to be neuroprotective in a model of cerebral ischemia and to prevent development of opioid-induced tolerance, both thought to be processes requiring plasticity. Preliminary data presented here demonstrates that exogenous agmatine reverses nerve injury- and inflammation-induced allodynia and hyperalgesia. The primary goal of the proposed study is whether endogenous agmatine participates in the control of spinally derived pain. The proposed studies will address that goal through pursuit of the following specific aims. 1). Determine the effect of endogenous agmatine in the spinal cord on nerve injury- and inflammation-induced hyperalgesia. The induction of behaviorally assessed allodynia and hyperalgesia will be compared across strains and conditions with differing agmatine concentration in spinal cord extracts. 2). Determine whether endogenous agmatine can be released from the spinal cord. Agmatine concentration in spinal cord dialysate will be compared prior to and following exposure to K+ and other depolarizing substances. 3). Determine how localization of agmatine in spinal cord and dorsal root ganglia (DRG) is related to that of other neurochemical markers. Antisera directed against agmatine will be used in laser confocal and electron microscopy studies to determine its regional, cellular, and ultrastructural localization in the spinal cord and DRG as well as its relationship to the localization of pain-related signaling molecules and proteins. 4.) Determine the relationship between agmatine and glutamate-mediated excitation in the spinal cord. Electrophysiological experiments will explore whether previously observed NMDA receptor channel blockade or other action accounts for agmatine's block of neuronal excitation and behavioral plasticity in spinal cord. The results of these studies will clarify the role of endogenous agmatine in nociception, its localization in relation to neurochemical markers of nociception, and its relationship to the excitatory nociceptive transmitter glutamate. The studies will also explore its participation as a novel neuromodulator of central sensitization. Elucidation of the role of the endogenous agmatine during hyperalgesia and allodynia may lead to the development of a novel class of analgesic drugs or the identification of therapeutic targets.

描述：(申请人提供) 本申请表是关于导师研究科学家发展奖(K01)的申请。 近年来，从哺乳动物中分离到了胍丁胺(脱羧精氨酸)。 大脑和脊髓。胍丁胺既能拮抗NMDA受体，又能抑制 一氧化氮合酶(NOS)。因为谷氨酸被认为可以驱动突触 通过一系列激活NMDA受体和NOS的可塑性，它是 可想而知，胍丁胺参与控制突触可塑性和 相关的行为现象(如学习和记忆、阿片类药物耐受性、 慢性疼痛)作为谷氨酸的神经调节剂。外源性给药 胍丁胺在脑缺血模型中被证明具有神经保护作用 以及防止阿片类药物诱导的耐受的发展，这两种方法都被认为是 需要可塑性的过程。这里提供的初步数据表明， 外源性胍丁胺逆转神经损伤和炎症诱导的痛觉过敏 痛觉过敏。拟议研究的主要目标是内生性 胍丁胺参与脊髓源性疼痛的控制。建议数 研究将通过追求以下具体目标来解决这一目标。 1)。测定脊髓内源性胍丁胺对神经的影响 损伤和炎症导致的痛觉过敏。行为的诱导性 评估的痛觉异常和痛觉过敏将在不同的菌株和 脊髓提取液中不同浓度胍丁胺的条件。2)。 确定内源性胍丁胺是否可以从脊髓中释放。 脊髓透析液中的胍丁胺浓度将在 在暴露于K+和其他去极化物质之后。3)。确定如何 胍丁胺在脊髓和背根神经节的定位 与其他神经化学标记物相关。抗血清 胍丁胺将用于激光共聚焦和电子显微镜研究 确定其在脑内的区域、细胞和超微结构定位 脊髓和背根神经节及其与脊髓损伤定位的关系 疼痛相关的信号分子和蛋白质。4.)确定关系 在胍丁胺和谷氨酸介导的脊髓兴奋之间。 电生理实验将探索之前观察到的NMDA 受体通道阻断或其他作用是胍丁胺阻断 脊髓神经元兴奋与行为可塑性。 这些研究的结果将阐明内源性胍丁胺在 伤害性感觉及其定位与神经化学标志物的关系 伤害性感觉及其与兴奋性伤害性递质的关系 谷氨酸。这些研究还将探索它作为一部小说的参与 中枢敏感化的神经调节剂。-阐明 痛觉过敏和痛觉异常时内源性胍丁胺可能导致 一类新型止痛药的开发或鉴定 治疗靶点。

项目成果

Pharmacodynamic and pharmacokinetic studies of agmatine after spinal administration in the mouse.

小鼠脊髓给药后胍丁胺的药效学和药代动力学研究。

• DOI: 10.1124/jpet.105.086173
• 发表时间: 2005
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Roberts,JohnC;Grocholski,BrentM;Kitto,KelleyF;Fairbanks,CarolynA
• 通讯作者: Fairbanks,CarolynA

Responsiveness of the Madison 109 lung carcinoma to maleic vinyl ether copolymer.

Madison 109 肺癌对马来酸乙烯基醚共聚物的反应性。

• DOI: 10.3109/08923978309026441
• 发表时间: 1983
• 期刊: Journal of immunopharmacology
• 作者: Klykken,PC;Loveless,SE;Morahan,PS;Munson,AE
• 通讯作者: Munson,AE