Vascular actions of peripheral CGRP in migraine-like photophobia in mice

Abstract

Background Calcitonin gene-related peptide is recognized as a key player in migraine, yet the mechanisms and sites of calcitonin gene-related peptide action remain unknown. The efficacy of calcitonin gene-related peptide-blocking antibodies as preventative migraine drugs supports a peripheral site of action, such as the trigeminovasculature. Given the apparent disconnect between the importance of vasodilatory peptides in migraine and the prevailing opinion that vasodilation is an epiphenomenon, the goal of this study was to test whether vasodilation plays a role in calcitonin gene-related peptide-induced light aversive behavior in mice. Methods Systemic mean arterial pressure and light aversive behavior were measured after intraperitoneal administration of calcitonin gene-related peptide and vasoactive intestinal peptide in wild-type CD1 mice. The functional significance of vasodilation was tested by co-administration of a vasoconstrictor (phenylephrine, endothelin-1, or caffeine) with calcitonin gene-related peptide to normalize blood pressure during the light aversion assay. Results Both calcitonin gene-related peptide and vasoactive intestinal peptide induced light aversion that was associated with their effect on mean arterial pressure. Notably, vasoactive intestinal peptide caused relatively transient vasodilation and light aversion. Calcitonin gene-related peptide-induced light aversion was still observed even with normalized blood pressure. However, two of the agents, endothelin-1 and caffeine, did reduce the magnitude of light aversion. Conclusion We propose that perivascular calcitonin gene-related peptide causes light-aversive behavior in mice by both vasomotor and non-vasomotor mechanisms.

PACAP Induces Light Aversion in Mice by an Inheritable Mechanism Independent of CGRP

“…However, a role for VPAC receptors in migraine pathology should not be discarded. We have shown that, similar to our results when testing PACAP-27, VIP can also induce light aversive behavior in mice if measured immediately after administration, consistent with its shorter half-life compared to PACAP (Mason et al, 2020). This suggests that the VPAC receptors are capable of inducing migraine-like phenotypes in mice, which has recently been validated by prolonged VIP infusion causing delayed headache in people (Pellesi et al, 2020).…”

CGRP induces migraine-like symptoms in mice during both the active and inactive phases

“…CGRP was diluted in modified Dulbecco PBS (Hyclone, GE Healthcare Life Science, USA), which was also used for vehicle groups. Except for the wheel assays for which animals were placed in the apparatus immediately after injection, for all other behavioral experiments, mice were allowed to recover for 30 min in their home cages before testing, in accordance with previously published data [ 19 , 20 ].…”

Photophobia and migraine outcome during treatment with galcanezumab

“…Neuropeptide CGRP has been found to be play a pivotal role in migraine pathogenesis ( 37 – 40 ). Moreover, various studies linked light aversive behavior in mice to CGRP, in both wild-type mice ( 41 ) and migraine models as hRAMP1 mice ( 42 , 43 ). The effect of CGRP on photophobia seems to be in part mediated by its vasomotor activity but in part independent of it ( 42 ).…”

“…Nonetheless, CGRP must also have non-vasomotor activities because some light aversive behavior was still observed in mice also in the presence of vasoconstrictors ( 41 ). At the vasculature, CGRP actions on smooth muscle and endothelium can potentially release cytokines, with consequent nociceptors sensibilization ( 47 ).…”