Slow Excitatory Phenomena - Interaction of Excitatory Amino Acids and Neuropeptides

疼痛的感知需要从初级传入感觉纤维到脊髓背角的次级投射神经元的兴奋性突触传递。两组候选神经递质被认为在疼痛通路中介导这一初始兴奋性步骤：一组是兴奋性氨基酸（EAA：谷氨酸，天冬氨酸），另一组是多肽（包括速激肽，如P物质和神经激肽A）。这些肽可能与同一神经元中的兴奋性氨基酸共定位。通过这些神经元的化学信号传递呈现出突触前（突触效能）和突触后（膜兴奋性）调节的新方面和复杂性，这在以前没有被考虑过，并且可能对体感觉，特别是疼痛通路的表现具有重要意义。Randic博士最近发现P物质和兴奋性氨基酸相互作用产生痛觉过敏的神经生理体征，即对兴奋性操作的反应延长增强。然而，肽信号产生增强EAA反应的位点和分子机制尚未阐明。Randic博士将研究不同的神经激肽受体的激活导致新分离的脊髓背角神经元对eaa，特别是对n -甲基- d -天冬氨酸（NMDA）的反应调节的假设。为了了解EAAs和速激肽之间相互作用的分子机制，将研究可能参与NMDA受体通道复合物甘氨酸变构位点，鸟嘌呤核苷酸结合蛋白（g蛋白）或Ca++敏感第二信使系统的变化。本研究将采用全细胞电压钳记录EAA反应。揭示多肽作用于脊髓背角神经元的细胞机制是了解脊髓背角解剖和神经化学组织的重要一步

The perception of pain requires excitatory synaptic transmission from primary afferent sensory fibers to secondary projection neurons in the dorsal horn of the spinal cord. Two groups of neurotransmitter candidates are thought to mediate this initial excitatory step in the pain pathway: one being excitatory amino acids (EAA: glutamate, asparate), and another are peptides (including tachykinins such as substance P and neurokinin A). These peptides may be colocalized with an excitatory amino acid(s) in the same neurons. Chemical signal transfer via such neurons presents new aspects and complexities of presynaptic (synaptic efficacy) and postsynaptic (membrane excitability) regulation which have not previously been considered and may have important implications for the performance of the somatosensory, especially of pain pathways. Dr. Randic has recently found that substance P and excitatory amino acids interact to produce neurophysiological signs of hyperalgesia i.e. a prolonged enhancement of responses to excitatory manipulation. However, the sites and the molecular mechanisms by which the peptide signals produce enhanced EAA responses have yet to be elucidated. Dr. Randic will examine the hypothesis that the activation of distinct neurokinin receptors causes modulation of the responses of freshly isolated spinal dorsal horn neurons to EAAs, especially to N-methyl-D-aspartic- acid (NMDA). To gain understanding of molecular mechanism(s) underlying interactions between EAAs, and tachykinins possible involvement of glycine allosteric site of NMDA receptor channel complex, guanine nucleotide-binding proteins (G-proteins) or change in Ca++-sensitive second messenger systems, will be investigated. Whole-cell voltage-clamp recording of EAA responses will be utilized in this study. Delineating the cellular mechanism(s) of peptide actions on dorsal horn neurons is an important step toward understanding anatomical and neurochemical organization of the spinal dorsal horn.***//