Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α2-adrenoceptors and 5-HT1 receptors

• Published in: Journal of headache and pain 2018-05, Vol.19 (1), p.1-10, Article 40
• Main Authors: González-Hernández, Abimael, Lozano-Cuenca, Jair, Marichal-Cancino, Bruno A., MaassenVanDenBrink, Antoinette, Villalón, Carlos M.
• Format: Article
• Language: English
• Subjects: Adrenergic receptors; Antagonists; Blood pressure; Calcitonin gene-related peptide; CGRP; Dihydroergotamine; Dopamine D2 receptors; Electrical stimuli; Frequency dependence; Haloperidol; Internal Medicine; Medicine; Medicine & Public Health; Neurology; Pain Medicine; Pithed rat; Research Article; Rodents; Sensory neurons; Serotonin S1 receptors; Vasoconstriction; Vasodepressor responses
• ISSN: 1129-2369; 1129-2377
• DOI: 10.1186/s10194-018-0869-8

Background 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 2A/2C -adrenergic, serotonin 5-HT 1B/1F , or dopamine D 2 -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. Methods 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 9 -T 12 ) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure. Results 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 2 -adrenoceptor; 310 μg/kg) plus GR127935 (5-HT 1B/1D ; 31 μg/kg); and (ii) remained unaffected after rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D 2 -like; 310 μg/kg) given alone, or after the combination of rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses. Conclusion DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional rauwolscine-sensitive α 2 -adrenoceptors and GR127935-sensitive 5-HT 1B/1D receptors, which correlate with α 2A/2C -adrenoceptors and 5-HT 1B 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.