Inger Jansen Olesen, Saurabh Gupta, Louise Juhl Boni, Kenneth Beri Ploug, Helle Wulf, Michael Baun, Maja Myren, Dipak Vasantrao Amrutkar, Deepak Kumar Bhatt, Roshni Ramachandran, Jes Olesen.
We have during the last 20 years studied the pharmacology of isolated cranial blood vessels from animals and humans in vitro. This work has led to several publications on the characterization of cerebrovascular receptors for 5-hydroxytryptamine and the sensory neuropeptides calcitonin gene-related peptide and substance P.
During the last 5-8 years we have introduced new techniques, giving us the ability to study the expression of mRNA and proteins for specific receptors in migraine relevant tissue. In addition, we have established the genuine closed cranial window technique.
This method allows us to perform in vivo measurements of the effect of a drug on pial and dural arteries when administered intravenously. We have further developed the method such it is possible to give drugs by intracarotid infusion.
The episodic nature of migraine attacks suggests that ion channels are involved in its pathophysiology. This is confirmed by finding the mutation in patients suffering from familial hemiplegic migraine within three different ion channel genes identified to date. Potassium channels have an important role in the regulation of vascular tone and an opener of ATP sensitive potassium (K(ATP)) channels has in clinical trials been found to induce headache.
An other channel we find might be important in migraine pathophysiology are the large conductance calcium activated potassium (BK(Ca)) channel. Furthermore, the receptors for vasoactive peptides and prostanoids such as vasoactive intestinal peptide (VIP) and pituitaty adenylyl cyclase activating peptide (PACAP), calcitonin gene-related peptide (CGRP), prostaglandin E2 and prostacyclin are of interest.
The aim of the current projects is to explore the subunit composition and role of these ion channels and receptors in pial and meningeal arteries and trigeminal ganglion. We have during the last three months of the year initiated three new projects. In these projects we investigate C-Fos expression after infusion of migraine triggering substances, the occurrence and mechanisms behind CGRP uptake in migraine relevant tissue and to investigate the presence and role of the proteinase activated receptor-2 in migraine relevant tissue.
The studies will give us an understanding of which subtype compositions of ion channels and receptors that are present in theses tissues. In addition, they will give us information to further understand the pathophysiology of migraine and to define new targets for the pharmacological treatment of migraine.
Lars Edvinsson (Department of Experimental Clinical Research, Glostrup Hospital) Anders Hay-Schmidt (Panum Institute, Copenhagen University), Dan Klærke (Faculty of Life Sciences, Copenhagen University), Majid Sheykhzade (Faculty of Pharmaceutical Sciences, Copenhagen University), Karl Messlinger (Institute of Physiology and Experimental Pathophysiology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany).