Second messenger signalling bypasses CGRP receptor blockade to provoke migraine attacks in humans

Abstract

There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine.

Keywords: PACAP; calcitonin; cranial arteries; migraine model; vasodilation.

Figure 1

Study design. Participants were enrolled in a randomized, double-blind, placebo-controlled, parallel trial. Participants were randomly allocated to a subcutaneous administration of 140 mg of erenumab or placebo (isotonic saline). Seven to 21 days after study drug administration, participants were randomly allocated to receive a continuous intravenous infusion of 1.5 μg/min of calcitonin gene-related peptide (CGRP) over 20 min or oral intake of 200 mg cilostazol on separate experimental study days.

Figure 2

Flow chart of participant recruitment of individuals with migraine. To study the effects of calcitonin gene-related peptide (CGRP) receptor blockade on experimentally induced migraine attacks, we administered erenumab or placebo to adults with migraine in a randomized, double-blind, placebo-controlled, parallel trial design.

Figure 3

Headache characteristics after administration of calcitonin gene-related peptide (CGRP) in individuals with migraine randomized to erenumab or placebo. Participants were randomized to erenumab or placebo 7–21 days prior to administration of CGRP. Headache intensity was rated on an 11-point numeric rating scale from 0 to 10 (median, thick lines). The median time to onset of migraine attack was 240 min (range: 30–540 min) in the erenumab group and 40 min (range: 10–480 min) in the placebo group. The median time to intake of rescue medication was 240 min (range: 120–660 min) in the erenumab group and 150 min (range: 40–480 min) in the placebo group. Square markers represent individual reported headache intensity.

Figure 4

Headache characteristics after administration of cilostazol in individuals with migraine randomized to erenumab or placebo. Participants were randomized to erenumab or placebo 7–21 days prior to administration of cilostazol. Headache intensity was rated on an 11-point numeric rating scale from 0 to 10 (median, thick lines). The median time to onset of migraine attack was 240 min (range: 10–600 min) in the erenumab group and 300 min (range: 20–600 min) in the placebo group. The median time to intake of rescue medication was 300 min (range: 120–720 min) in the erenumab group and 390 min (range: 70–600 min) in the placebo group. Square markers represent individual reported headache intensity.

Figure 5

Haemodynamic changes following administration of calcitonin gene-related peptide (CGRP) in individuals with migraine randomized to erenumab or placebo. (A) Mean change in diameter of the superficial temporal artery relative to baseline. The increase in the diameter of the superficial temporal artery in individuals randomized to erenumab was significantly less compared to placebo (P < 0.00001). Erenumab, however, did not completely inhibit the increase in diameter as there was a small increase compared to historical data with saline infusion in individuals with migraine without preventive medication. (B) Mean change in diameter of the radial artery relative to baseline. The increase in the diameter of the radial artery in individuals randomized to erenumab was significantly less compared to placebo (P < 0.00001). Erenumab, however, did not appear to completely inhibit the increase in diameter as there was a small increase compared to historical data with saline infusion in individuals with migraine without preventive medication. (C) Mean heart rate in absolute values. There was a significant increase in the heart rate in individuals randomized to placebo compared to erenumab (P < 0.00001). (D) Mean arterial pressure in absolute values. There was a significant decrease in the mean arterial pressure in individuals randomized to placebo compared to erenumab (P < 0.01). Error bars represent standard deviation. Historical data, A and B.

Figure 6

Haemodynamic changes following administration of cilostazol in individuals with migraine randomized to erenumab or placebo. (A) Mean change in diameter of the superficial temporal artery relative to baseline. There was no difference in the diameter of the superficial temporal artery in individuals randomized to erenumab compared to placebo (P = 0.238). (B) Mean change in diameter of the radial artery relative to baseline. There was no difference in the diameter of the radial artery in individuals randomized to erenumab compared to placebo (P = 0.984). (C) Mean heart rate in absolute values. There was no difference in the heart rate in individuals randomized to erenumab compared to placebo (P = 0.659). (D) Mean arterial pressure in absolute values. There was no difference in the mean arterial pressure in individuals randomized to placebo compared to erenumab (P = 0.480). Error bars represent standard deviation.