Transmitter release from peripheral sensory neurons

描述（由申请人提供）：专门用于检测伤害性刺激、温度和瘙痒的外周感觉神经，其外周末梢位于皮肤、肌肉、骨骼和内脏中，其胞体位于背根神经节（DRG）中，其中枢末梢位于脊髓背角中。刺激由小直径感觉神经元的AD和C纤维携带，其中许多表达有害热敏受体TRPV 1，一种Ca 2+渗透性阳离子通道。TRPV 1在DRG神经元的外周感觉末梢中作为多种伤害性刺激的主要换能器，包括43 ° C以上的伤害性热刺激。尽管TRPV 1在背角DRG神经元的中央突触末端上的存在已得到证实，但其在那里的生理相关性尚未明确确立。最近的研究结果表明，在某些条件下，TRPV 1可以在核心体温（~ 37 ℃）下变得活跃，远低于TRPVI正常的43 ℃激活温度阈值。第一个条件涉及温度和电压之间的相互作用。在静息膜电位下，TRPV 1在37 ℃下显示出可测量的紧张性激活。随后的去极化导致TRPV 1激活显著增加（Voets et al，2004）。然而，大多数TRPV 1在中央末梢功能的研究都是在室温而不是体温下进行的。其次，PLC偶联受体的活化导致TRPVI的活化温度阈值显著降低，导致其即使在室温下也被活化（Chuang等，2001）。我们建议测试的假设，在生理或体温下，无论是受体介导的PLC激活或生理膜去极化介导的动作电位和离子型受体递质的条件下，TRPV 1激活中枢感觉末梢是实质性的，这种激活将导致调制的DRG-脊髓突触的突触传递。这些研究集中在疼痛通路的一个关键部分;外周感觉纤维与中枢神经系统的交叉点，它们将为该通路的新调控机制提供见解。

DESCRIPTION (provided by applicant): The peripheral sensory nerves specialized for detection of noxious stimuli, temperature and itch have their peripheral terminals in the skin, muscle, bone and viscera, their cell bodies in the dorsal root ganglion (DRG), and their central terminals in the spinal dorsal horn. The stimuli are carried by AD and C-fibers of small diameter sensory neurons, many of which express the noxious heat-sensitive receptor, TRPV1, a Ca2+ permeable cation channel. TRPV1 in the peripheral sensory terminals of DRG neurons serves as a major transducer of multiple noxious stimuli, including noxious thermal stimuli above 43oC. Despite the well- established presence of TRPV1 on the central synaptic terminals of DRG neurons in the dorsal horn, its physiological relevance there has not been clearly established. Recent findings imply that under certain conditions, TRPV1 can be expected to become active at core body temperature (~37oC), well below TRPVI's normal 43oC temperature threshold for activation. The first condition involves the interaction between temperature and voltage. At resting membrane potentials, TRPV1 shows measurable, tonic activation at 37oC. Subsequent depolarization leads to substantial increases in TRPV1 activation (Voets et al, 2004). However, most investigations of TRPV1 function in central terminals have been carried out at room temperature rather than body temperature. Second, activation of PLC-coupled receptors leads to a dramatic reduction in TRPVI's temperature threshold of activation leading to its activation even at room temperature (Chuang et al, 2001). We propose to test the hypothesis that at physiological or body temperatures, and under the conditions of either receptor mediated PLC activation or physiological membrane depolarization mediated by action potentials and ionotropic receptor transmitters, TRPV1 activation in central sensory terminals is substantial and that this activation will lead to modulation of synaptic transmission at DRG-spinal cord synapses. These studies focus on a critical part of the pain pathway; the intersection of the peripheral sensory fiber with the central nervous systems and they will provide insight into new regulatory mechanisms in that pathway.