Goadsby P J, Hoskin K L
Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK.
Ann Neurol. 1998 Jun;43(6):711-8. doi: 10.1002/ana.410430605.
The development of serotonin (5HT1B/1D) agonists as treatments for the acute attack of migraine has resulted in considerable interest in their mechanism of action and, to some extent, renewed interest in the role of serotonin (5-hydroxytryptamine; 5HT) in the disorder. The initial synthesis of this class of compounds was predicated on the clinical observation that intravenous 5HT terminated acute attacks of migraine. In this study the superior sagittal sinus was isolated in the alpha-chloralose (60 mg/kg i.p. and 20 mg/kg i.v. injection supplementary 2 hourly) anesthetized cat. The sinus was stimulated electrically (120V, 250 microsec duration, 0.3 Hz), and neurons of the trigeminocervical complex in the dorsal C2 spinal cord were monitored using electrophysiological methods. After baseline recordings in each animal, 5HT (15 microg/kg/min) was infused for 5 minutes in the presence of either vehicle (group A) or the 5HT1B/1D antagonist GR127935 (100 microg/kg i.v. injection; group B). The baseline probability of cell firing after sagittal sinus stimulation was 0.61 +/- 0.1 at a latency to the fastest peak of 11.1 +/- 0.4 msec. In group A, 5HT infusion alone had a small effect of increasing mean blood pressure (12 +/- 3 mm Hg), which in itself did not alter cell firing. In group A, 5HT alone had an inhibitory effect on evoked trigeminal activity, which developed 15 to 20 minutes after commencement of the infusion. The inhibition of cell firing lasted for 20 minutes, after which the activity returned to baseline. In group B, the combination of 5HT and GR127935 had no effect on trigeminal cell firing, although the small hypertensive effect was still present. These data indicate that 5HT inhibits evoked trigeminal nucleus firing via the 5HT1B/1D receptor at which GR127935 is an antagonist. It is likely that some part of the effect of 5HT in migraine relates to inhibition of trigeminal nucleus activity, just as it is likely that some part of the effect of the triptans is also mediated at this central site and may be complementary to their nonneuronal actions. Moreover, the data highlight the case for describing this class of headache as neurovascular headaches rather than vascular headaches, to recognize the implicit contribution of the trigeminovascular system to their pathophysiology.
5-羟色胺（5HT1B/1D）激动剂作为偏头痛急性发作的治疗药物，引发了人们对其作用机制的浓厚兴趣，并且在一定程度上重新唤起了对5-羟色胺（5-羟色胺；5HT）在该疾病中作用的关注。这类化合物的最初合成是基于静脉注射5HT可终止偏头痛急性发作这一临床观察。在本研究中，在腹腔注射α-氯醛糖（60mg/kg，静脉注射补充20mg/kg，每2小时一次）麻醉的猫身上分离出上矢状窦。对上矢状窦进行电刺激（120V，持续时间250微秒，频率0.3Hz），并使用电生理方法监测颈髓背侧C2节段三叉神经颈复合体中的神经元。在每只动物进行基线记录后，在给予溶剂（A组）或5HT1B/1D拮抗剂GR127935（静脉注射100μg/kg；B组）的情况下，以15μg/kg/min的速度输注5HT持续5分钟。矢状窦刺激后细胞放电的基线概率在最快峰值潜伏期为11.1±0.4毫秒时为未0.61±0.1。在A组中，单独输注5HT对平均血压有轻微升高作用（12±3mmHg），而这本身并未改变细胞放电。在A组中，单独使用5HT对诱发的三叉神经活动有抑制作用，并在输注开始后15至20分钟出现。细胞放电的抑制持续20分钟，之后活动恢复到基线水平。在B组中，5HT与GR127935联合使用对三叉神经细胞放电无影响，尽管仍存在轻微的升压作用。这些数据表明，5HT通过GR127935作为拮抗剂的5HT1B/1D受体抑制诱发的三叉神经核放电。5HT在偏头痛中的部分作用可能与抑制三叉神经核活动有关，就像曲坦类药物的部分作用也可能在这个中枢部位介导，并且可能与其非神经元作用互补一样。此外，这些数据突出了将这类头痛描述为神经血管性头痛而非血管性头痛的理由，以认识到三叉神经血管系统对其病理生理学的潜在贡献。
