Hoskin K L, Goadsby P J
Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom.
Exp Neurol. 1998 Mar;150(1):45-51. doi: 10.1006/exnr.1997.6749.
The trigeminovascular system consists of bipolar neurons innervating pain-producing intracranial structures, such as the superior sagittal sinus (SSS), and projecting to the medullary and upper cervical dorsal horn second order neurons. Zolmitriptan is a newly developed 5HT1B/1D receptor agonist with both peripheral and central sites of action in the trigeminovascular system due to greater lipophilicity relative to the more hydrophilic antimigraine compound sumatriptan. Given that we have seen electrophysiological and autoradiographic binding data to suggest that the compound may inhibit activity at second-order neurons this study was designed to examine whether such an effect could be demonstrated in a population of trigeminal neurons using Fos immunohistochemistry. Cats were anesthetised with alpha-chloralose (60 mg/kg intraperitoneal then 20 mg/kg intravenous maintenance) with all surgery being conducted using halothane (1-3%). The animals were prepared for physiological monitoring, including blood pressure, heart rate, rectal temperature, and end-expiratory CO2. They were intubated, ventilated, and paralyzed with gallamine triethiodide (6 mg/kg i.v.). A midline craniotomy was performed to expose the sinus for electrical stimulation using hook electrodes. Twenty-four hours after completion of the surgical procedures the animal was ready for treatment. Vehicle, sumatriptan (85 micrograms/kg), or zolmitriptan (30 micrograms/kg) was administered and the SSS was stimulated (250 microseconds, 100 V at 0.3 Hz) for 1 h. Following an additional 1 h the animal was perfused and immunohistochemistry was used to detect the protein product of the immediate early gene c-Fos. We compared the dorsal horns of the medulla (trigeminal nucleus caudalis) and the C1 and C2 cervical spinal cords in control animals with those receiving zolmitriptan or sumatriptan. We noted a significant reduction in Fos expression after treatment with zolmitriptan but no effect with sumatriptan. Given that zolmitriptan accesses central neurons and that the method of stimulation we have employed would bypass peripheral trigeminal mechanisms it is likely that the reduction in second-order trigeminal neuronal activity was due to a direct inhibitory effect of the compound on those cells. These neurons form a possible site for the treatment of acute attacks of migraine.
三叉神经血管系统由双极神经元组成，这些神经元支配产生疼痛的颅内结构，如大脑上矢状窦（SSS），并投射到延髓和上颈段脊髓背角的二级神经元。佐米曲坦是一种新开发的5HT1B/1D受体激动剂，由于其亲脂性高于亲水性更强的抗偏头痛化合物舒马曲坦，因此在三叉神经血管系统中具有外周和中枢作用位点。鉴于我们已经看到电生理和放射自显影结合数据表明该化合物可能抑制二级神经元的活性，本研究旨在使用Fos免疫组织化学方法检查在一群三叉神经元中是否能证明这种效应。用α-氯醛糖（60mg/kg腹腔注射，然后20mg/kg静脉维持）麻醉猫，所有手术均使用氟烷（1-3%）进行。对动物进行生理监测准备，包括血压、心率、直肠温度和呼气末二氧化碳。对其进行插管、通气，并用三碘季铵酚（6mg/kg静脉注射）使其麻痹。进行中线开颅手术以暴露窦，使用钩形电极进行电刺激。手术程序完成24小时后，动物准备好接受治疗。给予赋形剂、舒马曲坦（85μg/kg）或佐米曲坦（30μg/kg），并刺激SSS（250微秒，100V，0.3Hz）1小时。再过1小时后，对动物进行灌注，并使用免疫组织化学检测即刻早期基因c-Fos的蛋白质产物。我们比较了对照动物与接受佐米曲坦或舒马曲坦的动物的延髓背角（三叉神经尾核）以及C1和C2颈脊髓。我们注意到用佐米曲坦治疗后Fos表达显著降低，但舒马曲坦没有效果。鉴于佐米曲坦可作用于中枢神经元，且我们采用的刺激方法会绕过外周三叉神经机制，因此二级三叉神经元活性的降低可能是由于该化合物对这些细胞的直接抑制作用。这些神经元可能是治疗偏头痛急性发作的一个位点。
