Fig. 7.

Schematic overview of the suggested role of CGRP and its antagonists in the gastrointestinal (GI) system. A Shows the normal situation with a low amount of free CGRP to stimulate the receptors B In a situation with high CGRP levels as described in [38] the CGRP molecules will bind to both CGRP-R and AMY₁-R. The higher affinity of CGRP to the CGRP-R leads to GI hyperactivity as observed during infusion of CGRP for 2 hrs [38]. In C inhibition of the CGRP molecules with monoclonal antibodies (e.g. Eptinezumab, Fremanezumab or Galcanezumab) is shown. Less free CGRP leads to a lower binding rate of CGRP to CGRP-R and AMY₁-R. The balance between signaling from CGRP-R and AMY₁-R is intact and neither GI-hyperactivity nor constipation is found. D Treatment of patients with erenumab a monoclonal antibody directed towards the CGRP-R, prevents binding of CGRP to the CGRP-R. Erenumab can to some extent also block the AMY₁-R. However, some CGRP molecules still binds to the free AMY₁-R. This situation causes an imbalance of CGRP signaling in the GI system with a larger inhibition of CGRP’s stimulating effect on CGRP-R than CGRP’s antagonistic effect on AMY₁-R. It should be noted that some of the AMY₁-R mediated effects on the GI-system can be secondary via receptors in area postrema. The overall effect is constipation, which has been reported during treatment with erenumab [30, 31]. E Future Real-World studies will reveal to what extent constipation occurs after treatment with small molecule antagonists such as Rimegepant. According to the results of the present study a similar pattern as described in C seems likely