REGULATION OF TRANSMITTER RELEASE IN THE DORSAL HORN

描述：谷氨酸和P物质由初级传入神经释放 背根神经节（DRG）的神经末梢的纤维传递 伤害性信号传递到中枢神经系统并调节疼痛 信号 DRG神经末梢突触前受体的激活 已经被假定为解释突触控制的一个关键水平， DRG传入神经元与其在背角中的靶点之间的耦合。 这些突触前调节受体中最著名的是 代谢型 例如，阿片和GABAB受体的激活， 已被建议抑制P物质和谷氨酸从 DRG神经末梢。 然而，离子型受体才刚刚开始 被认为是重要和强大的变送器释放调节器， 好. 最近的证据表明，ATP P2X受体有效地影响 谷氨酸从DRG神经末梢释放。 谷氨酸的释放是 检测到大量同步释放的谷氨酸 由再生动作电位活动驱动，或作为 mEPSC活性或谷氨酸量子释放的频率。 这些研究 提示DRG神经末梢附近ATP升高，其机制 包括Ca2+依赖性ATP释放或脊髓损伤后的释放， 将通过增加突触过程中谷氨酸的释放来增强信号输出。 传输 它也可能引起虚假的信号，导致疼痛信号 其实是从脊髓开始的 研究者 计划的解决两个主要的假设，从这些最初的 观察使用电生理和钙成像技术， 背根节与脊髓背角神经元突触传递研究 共培养和脊髓切片。 第一个要检验的假设是 突触前ATP P2X受体表达于DRG神经末梢 代表了一个重要的机制，用于调节释放的 递质谷氨酸和P物质以及P2X受体脱敏 是P2X受体活性依赖性的主要决定因素 突触前调节 背根神经节突触前ATP P2X受体的激活 神经末梢引起多个量子的大量同步释放， 当允许动作电位活动时，谷氨酸盐。 ATP诱导释放 当所有动作电位活动均被抑制时，可产生单量子谷氨酸盐。 我们将检验的第二个假设是，ATP是否能够使 DRG神经末梢通过激活Ca2+渗透性P2X受体，即 去极化启动DRG神经的动作电位活动 终端，这些动作电位需要的存在下， TTX抗性Na+通道。 本建议的研究结果将 这将有助于深入了解突触前P2X受体在感觉神经元中的作用。 信息处理以及阐明重要的药理学 为开发新的疼痛疗法提供了新的目标。

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.