Endogenous Agmatine in Glutamatergic Pain Processing

描述：（申请人提供） 此应用程序是一个指导研究科学家发展奖（K01）。 最近，胍丁胺（脱羧精氨酸）已从哺乳动物中分离出来， 大脑和脊髓胍丁胺既能拮抗NMDA受体， 一氧化氮合酶（NOS）。因为谷氨酸被认为是驱动突触 可塑性通过激活NMDA受体和NOS系列，它是 可以想象，胍丁胺参与控制突触可塑性， 相关的行为现象（例如学习和记忆，阿片类药物耐受， 慢性疼痛）作为谷氨酸的神经调节剂。外源施用的 胍丁胺已显示在脑缺血模型中具有神经保护作用 并防止阿片类药物诱导的耐受性的发展，两者都被认为是 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异常性疼痛， 痛觉过敏本研究的主要目的是研究是否是内源性的。 胍丁胺参与控制脊髓源性疼痛。拟议 研究将通过追求以下具体目标来实现这一目标。 1）。测定脊髓内源性胍丁胺对神经的影响 损伤和炎症引起的痛觉过敏。行为上的诱导 评估的异常性疼痛和痛觉过敏将在不同品系之间进行比较， 在脊髓提取物中具有不同胍丁胺浓度的条件。2）。 确定内源性胍丁胺是否可以从脊髓释放。 脊髓透析液中的胍丁胺浓度将在术前和术后进行比较。 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（DRG）的定位， 与其他神经化学标记物的关系。抗血清 胍丁胺将用于激光共聚焦和电子显微镜研究， 确定其区域，细胞和超微结构定位在 脊髓和背根神经节及其与神经节定位的关系 疼痛相关的信号分子和蛋白质。4.）确定关系 胍丁胺和谷氨酸介导的脊髓兴奋之间的关系。 电生理学实验将探索先前观察到的NMDA 受体通道阻滞或其他作用解释了胍丁胺阻断受体通道的作用。 脊髓神经元兴奋和行为可塑性。 这些研究的结果将阐明内源性胍丁胺在 伤害性感受，其定位与神经化学标记物的关系， 伤害感受及其与兴奋性伤害感受递质的关系 谷氨酸盐。这些研究还将探讨它作为一部小说的参与 中枢致敏的神经调质。阐明秘书长的作用 内源性胍丁胺在痛觉过敏和异常性疼痛可能会导致 开发一类新的镇痛药物或鉴定 治疗目标

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.