Departamento de Farmacobiología, Cinvestav-Coapa, Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, 14330, Ciudad de México, México.
Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus UNAM, Juriquilla, México.
J Headache Pain. 2018 May 25;19(1):40. doi: 10.1186/s10194-018-0869-8.
Dihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α-adrenergic, serotonin 5-HT, or dopamine D-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow.
Pithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 μg/kg·min) and DHE (3.1 μg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T-T) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure.
DHE inhibited the vasodepressor responses to electrical stimulation (0.56-5.6 Hz), without affecting those to i.v. α-CGRP (0.1-1 μg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists rauwolscine (α-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT; 31 μg/kg); and (ii) remained unaffected after rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D-like; 310 μg/kg) given alone, or after the combination of rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses.
DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional rauwolscine-sensitive α-adrenoceptors and GR127935-sensitive 5-HT receptors, which correlate with α-adrenoceptors and 5-HT receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE's vasoconstrictor properties resulting in an increased vascular resistance.
二氢麦角胺（DHE）是一种抗偏头痛药物，可引起颅脑血管收缩并抑制三叉神经 CGRP 释放；此外，它还抑制血管舒张感觉 CGRP 能传出，但涉及的受体仍不清楚。α-肾上腺素能、5-羟色胺 5-HT 或多巴胺 D 样受体的节前激活导致这种 CGRP 能传出的抑制。由于 DHE 对这些受体具有亲和力，因此本研究探讨了 DHE 诱导的抑制血管舒张感觉 CGRP 能传出的药理学特征。
预先用六烃季铵（2mg/kg·min）静脉内预处理去大脑僵直大鼠，然后连续输注甲氧胺（20μg/kg·min）和 DHE（3.1μg/kg·min）。然后，刺激-反应曲线（脊髓电刺激；T-T）或剂量-反应曲线（静脉内注射α-CGRP）导致舒张压呈频率依赖性或剂量依赖性下降。
DHE 抑制了对电刺激（0.56-5.6Hz）的血管舒张反应，而对静脉内注射的α-CGRP（0.1-1μg/kg）没有影响。DHE 的这种抑制作用（不是由甲氧胺输注产生的）：（i）用拮抗剂雷沃司琼（α-肾上腺素能受体；310μg/kg）加 GR127935（5-HT；31μg/kg）的组合预处理而被消除；（ii）在雷沃司琼（310μg/kg）、GR127935（31μg/kg）或氟哌啶醇（D 样；310μg/kg）单独给药后或在上述剂量的雷沃司琼加氟哌啶醇或 GR127935 加氟哌啶醇的组合后不受影响。
DHE 诱导的血管舒张感觉 CGRP 能传出的抑制主要由节前雷沃司琼敏感的α-肾上腺素能受体和 GR127935 敏感的 5-HT 受体介导，分别与 α-肾上腺素能受体和 5-HT 受体相关。这些发现表明，DHE 诱导的血管周围感觉 CGRP 能传出的抑制可能有助于 DHE 的血管收缩特性，导致血管阻力增加。
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