Second messenger signaling bypasses blockade of the calcitonin gene-related peptide (CGRP) receptor to provoke migraine attacks in humans

Abstract text (incl. figure legends and references)

Numerous endogenous molecules trigger migraine attacks when administered to humans. Of therapeutic importance, this has led to the concept of a "migraine attack signaling cascade" with the calcitonin gene-related peptide (CGRP) acting via a downstream second messenger cyclic adenosine monophosphate (cAMP) in intracranial vascular smooth muscle cells and other cells. However, whether intracellular cAMP signaling acts strictly downstream or is dependent on CGRP receptor activation during a migraine attack has never been tested directly in humans. Here, using a human provocation model (CGRP and phosphodiesterase 3 inhibitor, cilostazol, an agent known to accumulate intracellular cAMP by inhibiting its degradation) in a randomized, double-blind, placebo-controlled, parallel trial design, we demonstrate that migraine attacks can be provoked by intracellular cAMP-mediated mechanisms using cilostazol in the presence of CGRP receptor blockade (erenumab). Consistent with these findings, cilostazol-induced dilation of cranial arteries was unaffected by a CGRP receptor blockade. Our work provides clinical evidence that cAMP-evoked migraine attacks act downstream of the CGRP receptor, and that these cAMP-evoked migraine attacks appear independent of CGRP-receptor activation. These findings open new avenues for mechanism-based drug development for migraine.