Freedman J, Hökfelt T, Post C, Brodin E, Sundström E, Jonsson G, Terenius L, Leander S, Fischer J A, Verhofstad A
Department of Histology and Neurobiology, Karolinska Institutet, Stockholm, Sweden.
Exp Brain Res. 1989;74(2):279-92. doi: 10.1007/BF00248861.
Using behavioural, morphological and immunohistochemical analysis, the effect of intrathecal administration of a substance P antagonist, Spantide [D-Arg1, D-Trp7,9, Leu11)-SP), was studied. Antisera raised against markers for motoneurons, local spinal neurons, descending bulbospinal systems and primary afferents were used. The effect of some drugs, including thyrotropin releasing hormone (TRH), on Spantide-induced effects were also analyzed. After injection of 2 micrograms of Spantide at the lumbar level, a marked necrosis of the spinal cord was observed extending for about 5-6 segments, affecting mostly the ventral horns. Thus, calcitonin gene related peptide (CGRP)-like immunoreactivity (LI) in motoneurons completely disappeared and no motoneurons could be seen in cresyl violet-stained sections. The first changes were observed 6 h after Spantide injection and at 24 h a complete necrosis was seen. Marked reductions in the number of 5-hydroxytryptamine (5-HT)- and substance P-positive fibers were also observed. The effects were less dramatic in the dorsal horns, but at the site of maximal effects there was a disturbance also of CGRP-, substance P-, and neuropeptide tyrosine (NPY)-positive fibers in the superficial layers of the dorsal horn. These effects could be completely counteracted by multiple intravenous injections of TRH as well as with 5-methoxy-N, N-dimethyltryptamine (5-MeDMT), a 5-HT agonist. The behavioural analysis showed parallel changes, with permanent motor impairment after Spantide-treatment and complete absence of these symptoms when TRH or 5-MeDMT was given in addition. Finally, the effect of Spantide on 5-HT, noradrenaline, substance P and CGRP levels was measured biochemically. The present results are discussed in the light of recent findings that Spantide can cause a dramatic reduction in spinal blood flow.
采用行为学、形态学和免疫组织化学分析方法，研究了鞘内注射P物质拮抗剂Spantide [D-Arg1, D-Trp7,9, Leu11)-SP] 的作用。使用了针对运动神经元、脊髓局部神经元、下行延髓脊髓系统和初级传入神经标志物产生的抗血清。还分析了包括促甲状腺激素释放激素 (TRH) 在内的一些药物对Spantide诱导效应的影响。在腰段注射2微克Spantide后，观察到脊髓出现明显坏死，范围约为5 - 6个节段，主要影响腹角。因此，运动神经元中降钙素基因相关肽 (CGRP) 样免疫反应性 (LI) 完全消失，在甲酚紫染色切片中未见运动神经元。Spantide注射后6小时观察到最初变化，24小时出现完全坏死。还观察到5-羟色胺 (5-HT) 和P物质阳性纤维数量明显减少。背角的影响较小，但在最大效应部位，背角浅层的CGRP、P物质和神经肽Y (NPY) 阳性纤维也受到干扰。多次静脉注射TRH以及5-甲氧基-N, N-二甲基色胺 (5-MeDMT，一种5-HT激动剂) 可完全抵消这些效应。行为学分析显示出平行变化，Spantide治疗后出现永久性运动障碍，而额外给予TRH或5-MeDMT时这些症状完全消失。最后，通过生化方法测定了Spantide对5-HT、去甲肾上腺素、P物质和CGRP水平的影响。结合最近发现Spantide可导致脊髓血流量显著减少的研究结果，对本研究结果进行了讨论。
