Background: Migraine is a highly disabling neurovascular primary headache disorder,
with its exact pathomechanism being still unrevealed. The current leading hypotheses
are based on the sensitization and activation of the trigeminovascular system.
Objective: To review the literature with focus on the effects of kynurenines (L-kynurenine
and kynurenic acid) and pituitary adenylate cyclase-activating polypeptide on the regulation
of the trigeminovascular system.
Method: A literature search was conducted to identify preclinical and clinical publications
(198 references) by using the keywords ‘kynurenines’, ‘pituitary adenylate cyclase-activating
polypeptide’, and ‘migraine’ in the database of MEDLINE/PubMed up to 10 September 2016
for topical review. Additional filters used included ‘review’, ‘systematic review’, ‘original
article’, and ‘English language’.
Results: L-kynurenine and kynurenic acid act on the glutamatergic system at the level of the
second-order nociceptive neurons in the trigeminal nucleus caudalis. Pituitary adenylate cyclase-
activating polypeptide is released from the peripheral nerve endings of the trigeminal
pseudounipolar neurons and causes vasodilation and mast cell degranulation, leading to consequent
peripheral sensitization of the dural nociceptors. Centrally released pituitary adenylate
cyclase-activating polypeptide in the trigeminal nucleus caudalis results in the central
sensitization of the second-order neurons. The sensitization process leads to the characteristic
features of migraine.
Conclusion: L-kynurenine, kynurenic acid, and pituitary adenylate cyclase-activating polypeptide
may have fundamental roles in the initiation of migraine headache attacks.