Transmitter release from peripheral sensory neurons

描述(申请人提供)：专门用于检测伤害性刺激、温度和瘙痒的周围感觉神经，其外周终末位于皮肤、肌肉、骨骼和内脏，胞体位于背根节(DRG)，其中央终末位于脊髓背角。刺激由小直径感觉神经元的AD和C纤维携带，其中许多感觉神经元表达伤害性热敏受体TRPV1，一种钙离子渗透的阳离子通道。DRG神经元外周感觉终末的TRPV1是多种伤害性刺激的主要传递者，包括43oC以上的伤害性热刺激。尽管TRPV1存在于背角DRG神经元的中央突触终末，但其生理学相关性尚未明确。最近的发现表明，在某些条件下，TRPV1有望在核心体温(~37oC)下变得活跃，远低于TRPVI正常的43oC激活阈值。第一个条件涉及温度和电压之间的相互作用。在静止膜电位下，TRPV1在37oC时表现出可测量的紧张性激活。随后的去极化导致TRPV1激活的大幅增加(Voets等人，2004年)。然而，大多数关于TRPV1中枢终末功能的研究是在室温下进行的，而不是在体温下进行的。第二，PLC偶联受体的激活导致TRPVI的激活温度阈值显著降低，从而导致其即使在室温下也被激活(Chuang等人，2001)。我们提出的假设是，在生理或体温下，无论是在受体介导的PLC激活条件下，还是在动作电位和离子受体递质介导的生理性膜去极化条件下，TRPV1在中枢感觉终末都是大量激活的，这种激活将导致DRG-脊髓突触的突触传递的调节。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，它们将为深入了解该通路中的新调节机制提供依据。

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.