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.