Inger Jansen Olesen, Maja Myren, Dipak Vasantrao Amrutkar, Deepak Kumar Bhatt, Roshni ramachandran, Sara Hougaard Pedersen, Jes Olesen.
Using the human migraine models mentioned above, we receive knowledge about the headache provoking properties of endogenous signalling substances in man. We believe that a drug or substance that can block the effect of a headache/migraine provoking substance will be effective in the treatment of migraine and thus be a novel target for future development of medicine for migraine. Moving the studies of migraine triggering substances from man to animal we have the possibility to characterize the receptors or ion-channels for these substances in the migraine relevant tissues; cerebral arteries, dural arteries, dura mater, trigeminal ganglion and trigeminal nucleus caudalis. The characterization is performed by combining several different molecular and in vitro and in vivo functional studies.
- RT-PCR and in situ hybridization for investigating the presence of mRNA for different subtypes of receptors
- Western blotting and immunohistochemistry to investigate the presence and localization of protein for the different subtypes of the receptors and/or ion channels
- In vitro studies of the calcitonin gene-related peptide (CGRP) (a sensory peptide with a role in migraine pathophysiology) releasing properties of the migraine triggering substances in dura mater, trigeminal ganglion and trigeminal nucleus caudalis
- In vivo pharmacological characterization of the receptors activated in dural and pial arteries after intra carotid infusion of the migraine provoking substances
During infusion of a headache/migraine triggering substance the migraine sufferers experience more pain than non-migraineurs. This immediate headache is 4-5 hrs after the infusion followed by a delayed headache sometimes fulfilling the criteria for migraine. We have recently developed an animal model, where the migraine triggering substances are infused to un-anaesthetized rats and the molecular changes in the migraine relevant tissues mentioned above are investigated. By these studies we expect to unravel the cascade of molecular changes taking place in the time period between infusion of a migraine triggering substance and the development of a migraine attack.
At present we characterize the receptors for prostanoids and the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP) in migraine relevant tissues. We are in addition studying the effect of these substances on CGRP release and nitric oxide synthase (NOS) activity. In the conscious rat migraine model, we further examine what markers are up-regulated after infusion and the possible pathway for this up-regulation after infusion of migraine triggering substances. These studies will give us an understanding of which subtype of receptors that are present in these 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.
Professor Dan Klærke (Faculty of Life Sciences, Copenhagen University), Associate Professor Majid Sheykhzade (Faculty of Pharmaceutical Sciences, Copenhagen University), Professor Karl Messlinger (Institute of Physiology and Experimental Pathophysiology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany), Professor Frank Porreca (Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA), Professor Sue Duckles and Professor Diana Krause, Department of Pharmacology, University of California Irvine, Irvine, California, USA).