Ingvardsen B K, Laursen H, Olsen U B, Hansen A J
Department of General Pharmacology, Novo Nordisk A/S, Maaloev, Denmark.
Pain. 1997 Sep;72(3):407-15. doi: 10.1016/s0304-3959(97)00069-9.
Cortical spreading depression (CSD) is characterized by a transient, reversible depression of EEG activity which advances across the cortical surface at a velocity of 2-5 mm/min. CSD was originally linked to the aura phase of migraine, but recently also to migraine headache. The theory is that CSD activates meningeal trigeminal C-fibers causing neurogenic inflammation and pain (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177). The present study is an examination of the proposed link between CSD elicited in rats and activation of trigeminal nerve fibers. Multiple CSDs were elicited unilaterally for 1 h by KCl injections (1 M, 5 microliters) into the right hemisphere, while NaCl (1 M, 5 microliters) was injected into the left as control. After an additional 1 h the animals were sacrificed and trigeminal activation assessed by the expression of c-fos in trigeminal nucleus caudalis (TNC) using immunohistochemistry. The correlation between the number of CSDs and the extent of c-fos expression was determined. In addition the effect of sumatriptan (0.3 mg/kg) and morphine (3 mg/kg) given i.v. 30 min before elicitation of CSD was evaluated. CSD caused increased c-fos expression in lamina I and II of TNC where C-fibers, end, the response being greater ipsilaterally. Morphine, but not sumatriptan, reduced c-fos expression in both the ipsilateral and contralateral TNC by 71% (P < 0.05 and P = 0.19, respectively), confirming that nociceptors have been activated. No positive correlation was seen between the number of CSDs and the extent of c-fos expression in TNC. Instead we observed a positive, linear correlation between the number of KCl injections and the extent of c-fos expression in TNC (correlation coefficient r = 0.709, P < 0.05). We suggest that the C-fiber activation observed is caused by hyperosmolar KCl/NaCl and not CSD. Hence, our results do not support the hypothesis of Moskowitz et al. (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177) which links CSD with migraine headache.
皮层扩散性抑制（CSD）的特征是脑电图活动出现短暂、可逆的抑制，并以2-5毫米/分钟的速度在皮层表面传播。CSD最初与偏头痛的先兆期相关，但最近也与偏头痛性头痛有关。其理论是CSD激活脑膜三叉神经C纤维，导致神经源性炎症和疼痛（Moskowitz, M.A., Nozaki, K.和Kraig, R.P.，《新皮层扩散性抑制通过三叉神经血管机制激发三叉神经尾核内c-fos蛋白样免疫反应性的表达》，《神经科学杂志》，13卷（1993年）1167 - 1177页）。本研究旨在检验在大鼠中诱发的CSD与三叉神经纤维激活之间的假定联系。通过向右侧半球注射氯化钾（1 M，5微升）单侧诱发多次CSD，持续1小时，而向左侧注射氯化钠（1 M，5微升）作为对照。再过1小时后处死动物，使用免疫组织化学方法通过三叉神经尾核（TNC）中c-fos的表达评估三叉神经激活情况。确定CSD的次数与c-fos表达程度之间的相关性。此外，评估了在诱发CSD前30分钟静脉注射舒马曲坦（0.3毫克/千克）和吗啡（3毫克/千克）的效果。CSD导致TNC的I层和II层中c-fos表达增加，C纤维在此终止，同侧的反应更强。吗啡而非舒马曲坦使同侧和对侧TNC中的c-fos表达分别降低了71%（P分别<0.05和P = 0.19），证实伤害感受器已被激活。在CSD的次数与TNC中c-fos表达程度之间未观察到正相关。相反，我们观察到氯化钾注射次数与TNC中c-fos表达程度之间呈正线性相关（相关系数r = 0.709，P < 0.05）。我们认为观察到的C纤维激活是由高渗氯化钾/氯化钠引起的，而非CSD。因此，我们的结果不支持Moskowitz等人的假说（Moskowitz, M.A., Nozaki, K.和Kraig, R.P.，《新皮层扩散性抑制通过三叉神经血管机制激发三叉神经尾核内c-fos蛋白样免疫反应性的表达》，《神经科学杂志》，13卷（1993年）1167 - 1177页），该假说将CSD与偏头痛性头痛联系起来。
