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 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 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; T9-T12) 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 (α2-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT1B/1D; 31 μg/kg); and (ii) remained unaffected after rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D2-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 α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/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.

Additional Metadata
Keywords CGRP, Dihydroergotamine, Pithed rat, Sensory neurons, Vasodepressor responses
Persistent URL dx.doi.org/10.1186/s10194-018-0869-8, hdl.handle.net/1765/107354
Journal Journal of Headache and Pain
Citation
González-Hernández, A, Lozano-Cuenca, J, Marichal-Cancino, B.A, Maassen van den Brink, A, & Villalón, C.M. (2018). Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α2-adrenoceptors and 5-HT1 receptors. Journal of Headache and Pain, 19(1). doi:10.1186/s10194-018-0869-8