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Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of ?2-adrenoceptors and 5-HT1 receptors.

ABSTRACT: 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 ?2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-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 ?g/kg·min) and DHE (3.1 ?g/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of ?-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. ?-CGRP (0.1-1 ?g/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists rauwolscine (?2-adrenoceptor; 310 ?g/kg) plus GR127935 (5-HT1B/1D; 31 ?g/kg); and (ii) remained unaffected after rauwolscine (310 ?g/kg), GR127935 (31 ?g/kg) or haloperidol (D2-like; 310 ?g/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 ?2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with ?2A/2C-adrenoceptors and 5-HT1B 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.

SUBMITTER: Gonzalez-Hernandez A

PROVIDER: S-EPMC5970131 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

González-Hernández Abimael A Lozano-Cuenca Jair J Marichal-Cancino Bruno A BA MaassenVanDenBrink Antoinette A Villalón Carlos M CM

The journal of headache and pain 20180525 1

<h4>Background</h4>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 α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study inv ...[more]

PMID: 29802544

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Dataset Information

Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of ?2-adrenoceptors and 5-HT1 receptors.

Publications

Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α<sub>2</sub>-adrenoceptors and 5-HT<sub>1</sub> receptors.

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