Distribution of CGRP and CGRP receptor in the trigeminovascular system and CNS

Abstract: Calcitonin gene-related peptide (CGRP) has a key role in the pathophysiology of migraine and is associated with activation of the trigeminovascular system. Recently, CGRP receptor antagonists have been developed with clinical efficacy. The present thesis aimed therefore to investigate the distribution of CGRP and the CGRP receptor in the trigeminovascular system and in parts of the CNS. In the trigeminal ganglion, CGRP receptor was localized to neurons and satellite glial cells. CGRP was expressed in small/medium-sized neurons, which lacked CGRP receptor. This suggests that if CGRP is released within the ganglion, then intraganglionic CGRP may act on satellite glial cells and on large sized neurons. It was revealed that the trigeminal ganglion is not protected by the blood-brain barrier (BBB), suggesting that CGRP receptor antagonists may act here. In the periphery, expression of CLR and RAMP1 was found in the cranial, meningeal and cerebral arteries, and nerve fibers and rodent mast cells within the dura mater. Indeed we have uncovered that sensory nerves exist in two separate fiber populations and this has not been demonstrated before with such clarity. In the brainstem we identified certain regions expressing CGRP and its receptor. Brainstem regions, outside BBB, showed CGRP receptor binding, suggesting that CGRP receptor antagonists may act there independently from their ability to pass BBB. Rich expression of CGRP and CGRP receptor was detected in the cerebellum, pointing toward a functional role of CGRP in cerebellum. This research reveals the expression of CGRP receptor both at peripheral and central sites, implicating that many locations may be involved in migraine pathophysiology