Attenuation by valproate of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin
Attenuation by valproate of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin
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DOI：
10.1111/j.1476-5381.1995.tb15124.x
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发表时间：
1995-12-01
影响因子：
7.3
通讯作者：
Moskowitz, MA
中科院分区：
文献类型：
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作者：
Cutrer, FM;Limmroth, V;Moskowitz, MA
1 丙戊酸可用于治疗偏头痛，是一种 γ-氨基丁酸 (GABA) 转氨酶抑制剂和谷氨酸脱羧酶激活剂。其治疗偏头痛的机制仍不清楚。在脑池内注射刺激物辣椒素（0.1ml；15.25μgml（-1））后2小时，检查丙戊酸（2-丙基戊酸）对表达c-fos样免疫反应性（c-fos-LI）的细胞数量的影响，c-fos-LI是神经元激活的标志物，在三叉神经尾核（I，IIo；TNC）内。聚氨酯麻醉的哈特利豚鼠。对 90 只动物的 TNC 层 I、IIo 内的三个代表性水平（头端、中部和尾端）的 18 个切片 (50 μm) 中的阳性细胞进行计数。2 在辣椒素滴注后 (244+/-25; 1 ml; 15.25 mM) 对许多细胞进行标记，但在辣椒素媒介物 (11+/-1) 后未标记。内侧网状核、后区和孤束核内也发现阳性细胞。先前在应用脑池内刺激物（例如自体血或角叉菜胶）后已证明了类似的分布。3 丙戊酸（大于或等于 10 mg kg(-1)，腹膜内注射）使 I、IIo 层中的标记细胞减少 52%（P < 0.05），但在后区、孤束核或内侧网状核内则不然。先前在施用舒马曲坦、二氢麦角胺或NK1受体拮抗剂RPR 100,893.4后获得了类似的发现。用GABA(A)拮抗剂荷包牡丹碱(30μg kg(-1)；腹膜内注射)预处理，而不是GABA(B)拮抗剂法氯芬(1mg kg(-1))，逆转了丙戊酸的作用并增加了I层内的c-fos阳性细胞， IIo.有点矛盾的是，荷包牡丹碱本身（30 μ g kg(-1) i.p.）减少了标记细胞的数量，这表明不止一种 GABA 能机制可以抑制 c-fos 表达。5 我们得出结论，丙戊酸的作用机制是通过 GABA(A) 受体介导的。由于丙戊酸会降低 c-fos 的表达，并且如之前所示，会降低脑膜内的神经源性炎症，因此 GABA(A) 受体复合物可能为偏头痛和相关头痛的药物开发提供重要靶点。
1 Valproic acid, useful in the treatment of migraine, is an inhibitor of gamma-aminobutyric acid (GABA) aminotransferase and activator of glutamic acid decarboxylase. Its mechanism in migraine remains obscure. The effects of valproic acid (2-propylpentanoic acid) were examined on the number of cells expressing c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, within the trigeminal nucleus caudalis (lamina I, IIo; TNC) 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml; 15.25 mu g ml(-1)), in urethane-anaesthetized Hartley guinea-pigs. Positive cells were counted in eighteen sections (50 mu m) at three representative levels (rostral, middle and caudal) within lamina I, IIo of the TNC in 90 animals.2 Numerous cells were labelled after capsaicin instillation (244+/-25; 1 ml; 15.25 mM) but not after capsaicin vehicle (11+/-1). Positive cells were also found within the medial reticular nucleus, the area postrema and the nucleus of the solitary tract. A similar distribution has been demonstrated previously after application of intracisternal irritants such as autologous blood or carrageenin.3 Valproate (greater than or equal to 10 mg kg(-1), i.p.) reduced labelled cells by 52% (P < 0.05) in lamina I, IIo but not within the area postrema, the nucleus of the solitary tract or the medial reticular nucleus. A similar finding was obtained previously after administration of sumatriptan, dihydroergotamine or the NK1 receptor antagonist RPR 100,893.4 Pretreatment with bicuculline (30 mu g kg(-1); i.p.), a GABA(A) antagonist, but not phaclofen (1 mg kg(-1)) a GABA(B) antagonist, reversed the effect of valproate and increased c-fos positive cells within lamina I, IIo. Somewhat paradoxically, bicuculline by itself (30 mu g kg(-1) i.p.) decreased the number of labelled cells suggesting that more than a single GABAergic mechanism can suppress c-fos expression.5 We conclude that the mechanism of action of valproate is mediated via GABA(A) receptors. Since valproate decreases both c-fos expression and as previously shown, neurogenic inflammation within the meninges, the GABA(A) receptor complex might provide an important target for drug development in migraine and related headaches.