REGULATION OF TRANSMITTER RELEASE IN THE DORSAL HORN

描述：谷氨酸和P物质由初级传入释放 背根神经节(DRG)神经末梢的纤维传递 传递给中枢神经系统和调节疼痛的伤害性信号 发信号。背根神经节神经末梢突触前受体的激活 被认为是突触控制的一个关键水平 背根神经节传入神经元与其在背角的靶细胞之间的偶联。 这些突触前调节受体中最为人所知的是 代谢型。例如，阿片剂和GABAB受体的激活， 已被认为可以抑制P物质和谷氨酸的释放 背根神经节神经末梢。然而，电离子受体才刚刚开始 被认为是发射器释放的重要和强大的调节器 井。最近的证据表明，ATPP2X受体可以有效地影响 从背根节神经末梢释放谷氨酸。谷氨酸的释放是 检测到大量的、同步释放的多量子谷氨酸 由再生动作电位活动驱动，或作为 MEPSC活性或量子谷氨酸释放的频率。这些研究 提示DRG神经末梢附近的ATP升高是通过一种机制 包括钙离子依赖的ATP释放或脊髓损伤后的释放， 将通过增加突触中谷氨酸的释放来增强信号输出 变速箱。它还可能引起虚假信号，导致疼痛信号。 实际上是在脊髓本身启动的。调查员 计划解决以下两个主要假设 应用电生理和钙离子成像技术观察 大鼠背根神经节与背角神经元间突触传递的研究 共培养和脊髓切片中。第一个要检验的假设是 突触前ATP2X受体在DRG神经末梢的表达 代表了一种重要的机制，用于规范 谷氨酸和P物质递质与P2X受体脱敏 是P2X受体活性依赖的主要决定因素 突触前调节。突触前ATP_2X受体对背根节的激活作用 神经末梢引起大量的同步释放多量子的 允许动作电位活动时的谷氨酸。三磷酸腺苷诱导细胞释放 当所有动作电位活动被抑制时，单量子谷氨酸。 我们将测试的第二个假设是，ATP是否能够去极化 DRG神经末梢通过激活钙离子通透性的P2X受体， 去极化启动DRG神经的动作电位活动 以及这些动作电位需要存在 抗河豚毒素的钠离子通道。这项建议的研究结果将 为突触前P2X受体在感觉中的作用提供洞察力 信息处理以及阐明重要的药理作用 开发新的止痛疗法的目标。

DESCRIPTION: Glutamate and substance P are released by primary afferent fibers of the dorsal root ganglion (DRG) nerve terminals to transmit nociceptive signals to the central nervous system and to modulate pain signaling. Activation of presynaptic receptors on the DRG nerve terminal has been postulated to account for one critical level of control of synaptic coupling between the afferent DRG neuron and its target in the dorsal horn. The best known of these presynaptic regulatory receptors is of the metabotropic type. Activation of opiate and GABAB receptors, for example, has been suggested to inhibit release of substance P and glutamate from the DRG nerve terminal. However, ionotropic receptors are just beginning to be appreciated as important and powerful regulators of transmitter release as well. Recent evidence shows that ATP P2X receptors potently influence glutamate release from the DRG nerve terminal. The glutamate release is detected as large, synchronous release of multiple quanta of glutamate driven by regenerative action potential activity or as an increase in the frequency of mEPSC activity or quantal glutamate release. These studies suggest that elevation of ATP near the DRG nerve terminals, by a mechanism including Ca2+ dependent ATP release or release following spinal cord jury, will enhance signal output by increasing glutamate release during synaptic transmission. It may also evoke spurious signaling causing pain signals that are actually initiated in the spinal cord itself. The investigator plan's to address two main hypotheses that follow from these initial observations using electro-physiological and Ca2 imagining techniques to study synaptic transmission between DRG and dorsal horn neurons in co-culture and in spinal cord slices. The first hypothesis to be tested is that the presynaptic ATP P2X receptors expressed on DRG nerve terminals represent an important mechanism for regulating the release of the transmitters glutamate and substance P and that P2X receptor desensitization is a major determinant of the activity dependence of the P2X receptor presynaptic regulation. Activation of presynaptic ATP P2X receptors on DRG nerve terminals evokes a large synchronous release of multiple quanta of glutamate when action potential activity is allowed. ATP induces release of single quanta of glutamate when all action potential activity is suppressed. The second hypothesis we will test is whether ATP is able to depolarize the DRG nerve terminals by activation of Ca2+ permeable P2X receptors, that the depolarization initiates action potential activity at the DRG nerve terminal, and that these action potentials require the presence of TTX-resistant Na+ channels. The result of the studies in this proposal will be to provide insight on the role of presynaptic P2X receptors in sensory information processing as well as elucidate important pharmacological targets for the development of new pain therapies.