Cutrer F M, Moussaoui S, Garret C, Moskowitz M A
Stroke Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Neuroscience. 1995 Feb;64(3):741-50. doi: 10.1016/0306-4522(94)00428-8.
The effect of RPR 100893, a selective and specific neurokinin-1 antagonist, or its enantiomer RPR 103253 was examined on c-fos antigen expression in brain stem and upper cervical cord 2 h after intracisternal capsaicin injection (30.5 micrograms/ml) in pentobarbital-anesthetized Hartley guinea-pigs. Positive cells were counted at three levels corresponding to obex, -2.25 mm and -6.75 mm in 18 sections (50 microns). Immunoreactivity was strongly expressed within laminae I and IIo of trigeminal nucleus caudalis, area postrema and the leptomeninges. Moderate labeling was present in the nucleus of the solitary tract and the medullary lateral reticular nucleus, whereas few positive cells were found in the ventral portion of the medullary reticular nucleus and Rexed laminae III-V and X. The distribution of labeled cells was consistent with previously reported results following subarachnoid placement of the noxious agents, blood or carrageenin. Pretreatment with RPR 100893 (1, 10 and 100 micrograms/kg, i.v.) but not its enantiomer (100 micrograms/kg, i.v.) 30 min prior to capsaicin injection significantly reduced the number of positive cells in the trigeminal nucleus caudalis (P < 0.01) in a dose-dependent manner, but not within area postrema or nucleus of the solitary tract. These results indicate that (i) the instillation of capsaicin into the subarachnoid space is an effective stimulus for the induction of c-fos antigen within trigeminal nucleus caudalis, presumably through activation of trigeminovascular afferents, and (ii) the neurokinin-1 antagonist RPR 100893 reduces the number of positive cells selectively within this nucleus. The findings are significant because drugs which alleviate vascular headaches decrease the number of c-fos-positive cells within trigeminal nucleus caudalis following noxious meningeal stimulation. Hence, strategies aimed at blocking the neurokinin-1 receptor may be useful for treating migraine and cluster headache.
在戊巴比妥麻醉的Hartley豚鼠中，脑池内注射辣椒素（30.5微克/毫升）2小时后，研究了选择性特异性神经激肽-1拮抗剂RPR 100893或其对映体RPR 103253对脑干和颈髓上部c-fos抗原表达的影响。在18个切片（50微米）中，对应于闩、-2.25毫米和-6.75毫米的三个水平上对阳性细胞进行计数。免疫反应性在三叉神经尾核的I层和IIo层、最后区和软脑膜中强烈表达。孤束核和延髓外侧网状核中有中度标记，而在延髓网状核腹侧部分以及Rexed III-V层和X层中发现的阳性细胞很少。标记细胞的分布与先前报道的蛛网膜下腔放置有害剂、血液或角叉菜胶后的结果一致。在辣椒素注射前30分钟静脉注射RPR 100893（1、10和100微克/千克）而非其对映体（100微克/千克，静脉注射），以剂量依赖方式显著减少了三叉神经尾核中的阳性细胞数量（P<0.01），但在最后区或孤束核中没有减少。这些结果表明：（i）将辣椒素滴入蛛网膜下腔是诱导三叉神经尾核内c-fos抗原的有效刺激，可能是通过激活三叉神经血管传入神经；（ii）神经激肽-1拮抗剂RPR 100893选择性地减少了该核内的阳性细胞数量。这些发现具有重要意义，因为缓解血管性头痛的药物在有害性脑膜刺激后会减少三叉神经尾核内c-fos阳性细胞的数量。因此，旨在阻断神经激肽-1受体的策略可能对治疗偏头痛和丛集性头痛有用。
