title: The role of genetics on migraine induction triggered by CGRP and PACAP38.
abstract: Migraine has a strong genetic component and is characterized by multiphasic events including an initial premonitory phase with premonitory symptoms (PS). Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide-38 (PACAP38) are endogenous neuropeptides that can trigger migraine attacks and have in recent years gained considerable interest in the migraine field. Yet, the exact pathophysiological mechanisms underlying CGRP- and PACAP38-induced attacks are not fully clarified. Human provocation models have shown that these peptides induce attacks in only two- thirds of migraine patients. Whether this diverse migraine response after CGRP or PACAP38 may be explained by genetic factors is unknown. The present thesis includes four studies that explore different factors that may be associated with the CGRP- and PACAP38-induced migraine response. In study I and II we investigated the role of familial predisposition (family load) and number of risk conferring gene variants on migraine attacks induced by CGRP or PA-CAP38. In study III, we investigated biochemical changes of CGRP, vasoactive intestinal peptide (VIP), S100B and TNF-alpha in the blood after PACAP38. Finally in study IV, we studied whether CGRP or PACAP38 may induce PS. Study I and II demonstrated that PACAP38 and CGRP induce migraine attacks in 63% and 72% of the patients, respectively. Moreover, we showed that patients with high family load or a high number of migraine associated gene variants did not report more migraine attacks after CGRP or PACAP38 than those with no familial predisposition or few gene variants. Study III showed that PACAP38 infusion caused changes in plasma concentrations for VIP and S100B, but not CGRP and TNF-alpha, suggesting activation of parasympathetic nerve endings. Study IV showed absence of PS after CGRP and lack of statistical difference in PS between patients who reported and not reported attacks after PACAP38 suggesting peripheral mechanisms of induction. In conclusion, the present thesis suggests that genetics factors such as family load and genetic variants do not contribute to susceptibility of migraine attacks induced by CGRP or PACAP38. Additionally, our data indicate that CGRP and PACAP38 primarily have a peripheral site of action. We believe that the acquired knowledge from this thesis on how CGRP and PACAP38 might be involved in migraine pathophysiology would contribute to the development of novel and better migraine treatments in the future.
authors.affiliation: song.guo.01@regionh.dk.
authors.forename: Song
authors.initials: S
authors.lastname: Guo
mesh_terms: D000328:Adult; D000368:Aged; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D006261:Headache / Q000145:classification / Q000503:physiopathology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000097:blood / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D062706:Prodromal Symptoms; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D055815:Young Adult
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D015740:Calcitonin Gene-Related Peptide