Investigation of carbachol and PACAP38 in a human model of migraine.
The parasympathetic signalling molecules acetylcholine, pituitary adenylate cyclase activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) may be released from parasympathetic fibres and activate sensory nerve fibres during migraine attacks. Recently, it was shown that VIP does not induce migraine-like attacks in migraine patients. Interestingly, PACAP38 activates the same VPAC receptors as VIP, but also specifically activates the PAC1 receptor. The present thesis includes four double-blind placebo-controlled crossover studies aimed to explore the role of acetylcholine, PACAP and VIP in migraine and head pain. In study I-III we investigated acetylcholine, via the analogue carbachol, and PACAP38 in a human model of migraine. In study IV we studied if PACAP38 and VIP might induce central sensitization, neurogenic inflammation and mast cell degranulation in a cutaneous model of acute pain. Study I-II showed that carbachol induced short lasting mild headache and moderate cephalic vasodilatation in both healthy volunteers and migraine patients, but did not induce migraine-like attacks. In study III PACAP38 induced headache in healthy subjects and delayed migraine-like attacks in migraine patients as well as sustained dilatation of cephalic vessels. In study IV VIP and PACAP38 evoked skin pain, central sensitization, neurogenic inflammation and mast cell degranulation, but VIP showed to be more potent than PACAP38 in inducing neurogenic inflammation and mast cell degranulation. In conclusion, we found that carbachol infusion was not a good model for experimental migraine provocation, probably because the maximal dose was insufficient to produce enough nitric oxide to trigger migraine. PACAP38 infusion is a new pathway for migraine induction and the results from study IV suggest that neurogenic inflammation and mast cell degranulation are unlikely to cause PACAP38 induced migraine. The present thesis contributes to our knowledge on migraine pathophysiology and suggests PAC1 receptor antagonism as a new target for migraine treatment.
Danish Headache Center, Department of Neurology, Glostrup Hospital, Denmark. henrikschytz@hotmail.com
Henrik Winther
HW
Schytz
D000293:Adolescent; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D002217:Carbachol / Q000627:therapeutic use*; D002560:Cerebrovascular Circulation; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000627:therapeutic use*; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use*; D055815:Young Adult
D018712:Analgesics, Non-Narcotic; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014665:Vasodilator Agents; D002217:Carbachol