Young M R, Blackburn-Munro G, Dickinson T, Johnson M J, Anderson H, Nakalembe I, Fleetwood-Walker S M
Department of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, United Kingdom.
J Neurosci. 1998 Dec 1;18(23):10180-8. doi: 10.1523/JNEUROSCI.18-23-10180.1998.
Electrophysiological and behavioral studies point to a role of group I metabotropic glutamate receptors (mGluR1 and mGluR5) in mediating spinal nociceptive responses in rats. However, antagonists with a high degree of specificity for each of these sites are not yet available. We, therefore, examined the effects of antisense deletion of spinal mGluR1 expression in assays of behavioral analgesia and of electrophysiological responses of dorsal horn neurons. Rats treated with an mGluR1 antisense oligonucleotide reagent, delivered continuously to the intrathecal space of the lumbar spinal cord, developed marked analgesia as measured by an increase in the latency to tail-flick (55 degreesC) over a period of 4-7 d. This correlated with a selective reduction in mGluR1, but not mGluR5, immunoreactivity in the superficial dorsal horn compared with untreated control rats, in parallel with a significant reduction in the proportion of neurons activated by the mGluR group I agonist 3, 5-dihydroxyphenylglycine (DHPG), whereas the proportion of cells excited by the mGluR5 agonist, trans-azetidine-2,4-dicarboxylic acid (t-ADA) remained unaffected. In contrast, rats treated with mGluR1 sense or mismatch probes showed none of these changes compared with untreated, control rats. Furthermore, multireceptive dorsal horn neurons in mGluR1 antisense-treated rats were strongly excited by innocuous stimuli to their peripheral receptive fields, but showed severe reductions in their sustained excitatory responses to the selective C-fiber activator mustard oil and in responses to DHPG.
电生理学和行为学研究表明，I 型代谢型谷氨酸受体（mGluR1 和 mGluR5）在介导大鼠脊髓伤害性反应中发挥作用。然而，目前尚无对这些位点具有高度特异性的拮抗剂。因此，我们在行为镇痛测定以及背角神经元电生理反应测定中，研究了脊髓 mGluR1 表达的反义缺失效应。用 mGluR1 反义寡核苷酸试剂连续注入大鼠腰段脊髓鞘内，在 4 - 7 天的时间里，通过甩尾潜伏期（55℃）延长来衡量，大鼠出现了明显的镇痛效果。与未处理的对照大鼠相比，这与浅层背角中 mGluR1 免疫反应性的选择性降低相关，但 mGluR5 免疫反应性未受影响，同时，由 I 型 mGluR 激动剂 3,5 - 二羟基苯甘氨酸（DHPG）激活的神经元比例显著降低，而由 mGluR5 激动剂反式 - 氮杂环丁烷 - 2,4 - 二羧酸（t - ADA）激发的细胞比例未受影响。相比之下，与未处理的对照大鼠相比，用 mGluR1 正义或错配探针处理的大鼠未出现这些变化。此外，mGluR1 反义处理大鼠中的多感受性背角神经元受到无害刺激对其外周感受野的强烈兴奋，但对选择性 C 纤维激活剂芥子油的持续兴奋性反应以及对 DHPG 的反应均显著降低。
