PERIPHERAL AND CENTRAL TRIGEMINOVASCULAR ACTIVATION IN CAT IS BLOCKED BY THE SEROTONIN (5HT)-1D RECEPTOR AGONIST 311C90
PERIPHERAL AND CENTRAL TRIGEMINOVASCULAR ACTIVATION IN CAT IS BLOCKED BY THE SEROTONIN (5HT)-1D RECEPTOR AGONIST 311C90
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DOI：
10.1111/j.1526-4610.1994.hed3407394.x
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发表时间：
1994-07-01
期刊：
影响因子：
5
通讯作者：
EDVINSSON, L
中科院分区：
文献类型：
--
作者：
GOADSBY, PJ;EDVINSSON, L
偏头痛涉及三叉神经传入神经的激活，三叉神经传入神经主要存在于神经的第一分支或眼分支。头痛通常是剧烈的，因此三叉神经和三叉血管系统的连接与偏头痛的病理生理有关，并得到了广泛的研究。人们对该系统的外围分支作为抗偏头痛药物的可能作用点给予了相当大的关注，而对可能的中心作用点的关注却很少。研究表明，某些肽可以作为三叉神经系统的标志物，特别是降钙素基因相关肽（CGRP），而CGRP在偏头痛中升高。我们采用了激活三叉神经血管系统的动物模型来评估一种新的抗偏头痛化合物311C90，它可能具有中枢和外周三叉神经的作用。猫采用氟烷诱导和α -氯蔗糖维持麻醉（60 mg/kg，腹腔），插管、麻痹和通气。采用双顶骨开颅术，用激光多普勒血流仪（CBF(LDF)）测量脑血流。颈外静脉插管，抽血，离心，冷冻，待处理。刺激三叉神经节导致CBF（LDF）在20/s时平均最大增加39 +/- 5%。5HT1激动剂311C90以两种剂量（30和100马克杯/公斤）静脉注射，以覆盖临床可能有效的剂量范围。在每次剂量下，三叉神经节刺激的CBF（LDF）效应均被抑制。刺激三叉神经节导致颈外静脉降钙素基因相关肽和血管活性肠多肽（VIP）水平升高。以100马克杯/公斤的剂量施用311C90后，这两种症状都明显减弱。在研究过程中，神经肽Y和-内啡肽均未发生变化。这些数据表明，三叉神经节刺激导致CBF（LDF）的剧烈变化，这可以通过311C90调节。此外，VIP释放的抑制表明该药物对三叉神经尾核突触的作用，表明该中心部位可能对311C90在偏头痛中的作用具有重要优势。
Migraine headache involves the activation of trigeminal afferents that are predominantly found in the first or ophthalmic division of the nerve. The headache is often pounding and the connections of the trigeminal nerve, the trigeminovascular system, have therefore been implicated in the pathophysiology of migraine and studied extensively. Considerable attention has been given to the peripheral ramifications of the system as a possible locus of action for anti-migraine drugs while little attention has been focused upon possible central sites of action. It has been shown that certain peptides can act as markers for the trigeminal system, in particular calcitonin gene-related peptide (CGRP), and that CGRP is elevated in migraine. We have employed an animal model for activation of the trigeminovascular system to evaluate a new anti-migraine compound, 311C90, that may have central and as well as peripheral trigeminal actions. Cats were anesthetized by halothane induction and alpha-chloralose maintenance (60 mg/kg, intraperitoneal), intubated, paralyzed and ventilated. Biparietal craniotomies were carried out to measure cerebral blood flow using laser Doppler flowmetry (CBF(LDF)). The external jugular vein was cannulated and blood drawn, centrifuged and frozen until processing. Stimulation of the trigeminal ganglion resulted in a mean maximum increase in CBF(LDF) of 39 +/- 5% at 20/s. The 5HT1 agonist 311C90 was administered intravenously in two doses (30 and 100 mug/kg) to cover the range of doses likely to be effective clinically. At each dose the CBF(LDF) effect of trigeminal ganglion stimulation was inhibited. Stimulation of the trigeminal ganglion led to increases in both calcitonin gene-related peptide and vasoactive intestinal polypeptide (VIP) levels in the external jugular vein. These were both attenuated markedly by administration of 311C90 in a dose of 100 mug/kg. No change in either neuropeptide Y or beta-endorphin were seen during the study. These data demonstrate that trigeminal ganglion stimulation results in a brisk change in CBF(LDF) that can be modulated by 311C90. Furthermore the inhibition of VIP release indicates an action of the drug st the synapse in the trigeminal nucleus caudalis suggesting that this central site may have important advantages for the action of 311C90 in migraine.