Messenger molecules and receptors in the human trigeminovascular system

Sammanfattning: The initiation of a migraine attack involves a primary central nervous system dysfunction with subsequent activation of the trigeminovascular system. In trigeminal ganglia, the expression of calcitonin gene-related peptide (CGRP), substance P (SP) and nitric oxide synthase (NOS) have been demonstrated by immunocytochemistry. During migraine attacks, the level of released CGRP is increased. Meanwhile, clinical trials have shown that 5-HT receptor agonists can alleviate headache by the inhibition of the release of CGRP from the sensory nervous system. Although there is no evidence of increased levels of SP or NO during migraine, the involvement of SP and NO in migraine has been suggested by different ways. A NOS inhibitor inhibits migraine while a NO donor causes migraine. While SP is not involved in early attacks, it may come later and be responsible for neurogenic inflammation. In this thesis, the aims were to study the distribution of 5-HT1B and 5-HT1D receptors, the capsaicin receptor and nociceptin as well as their co-localization with CGRP, SP or NOS. All the studied receptors and nociceptin were localized in the human trigeminal ganglion and they were mainly present in medium-sized neuronal cell bodies. The existence of the capsaicin receptor and the nociceptin receptor in addition has also been studied at the mRNA level in human trigeminal ganglia and in cerebral arteries by RT-PCR. They existed in human trigeminal ganglia but not in human cerebral arteries. This was further confirmed by in vitro pharmacology, which showed no vasomotor effect in human cerebral arteries by nociceptin. All the studied receptors and nociceptin were co-localized with CGRP, SP and NOS. In this thesis, we also characterized the vasoconstrictory effect of the P2Y6 receptor in human cerebral arteries by in vitro pharmacology. The RT-PCR was used to confirm the existence of P2Y6 receptors in the human cerebral artery, putatively this may indicate a new anti-migraine mechanism. Further study detected that P2Y6 receptors can induce proliferation of vascular smooth muscle cells, via phospholipase C, protein kinase C delta and a tyrosine kinase pathway. Quantitative competitive RT-PCR revealed that P2Y6 receptor mRNA is rapid turnover and is regulated by growth factors that can be released under physiological and pathophysiological conditions.