Activation of iGluR5 kainate receptors inhibits neurogenic dural vasodilatation in an animal model of trigeminovascular activation

Migraine is a disabling neurological disorder involving activation, or the perception of activation, of trigeminovascular afferents containing calcitonin gene-related peptide (CGRP). Released CGRP from peripheral trigeminal afferents causes dilatation of dural blood vessel, and this is used to measure trigeminal nerve activation. Kainate receptors with the GluR5 subunit (iGluR5, ionotropic glutamate receptor) are present in the trigeminal ganglion and may be involved in nociception. We investigated the possible involvement of prejunctional iGluR5 kainate receptors on CGRP release from trigeminal afferents. We used neurogenic dural vasodilatation, which involves reproducible vasodilatation in response to CGRP release after electrical stimulation of the dura mater surrounding the middle meningeal artery. The effects of the specific iGluR5 receptor antagonist UBP 302 and agonist (S)-(-)-5-iodowillardiine were investigated on neurogenic and CGRP-induced dural vasodilatation in rats, by using intravital microscopy. Administration of 10 and 20 mg.kg(-1) of iodowillardiine inhibited electrically induced dural vessel dilatation, an effect blocked by pretreatment with 50 mg.kg(-1) UBP 302. Administration of the iGluR5 receptor antagonist UBP 302 alone had no significant effect. CGRP (1 mg.kg(-1))-induced dural vasodilatation was not inhibited by the iGluR5 receptor agonist iodowillardiine. This study demonstrates that activation of the iGluR5 kainate receptors with the selective agonist iodowillardiine is able to inhibit neurogenic dural vasodilatation probably by inhibition of prejunctional release of CGRP from trigeminal afferents. Taken together with recent clinical studies the data reinforce CGRP mechanisms in primary headaches and demonstrate a novel role for kainate receptor modulation of trigeminovascular activation.