New insights into the molecular actions of serotonergic antimigraine drugs.
Migraine is a painful and debilitating neurological disorder that affects approximately 10% of the adult population in Western countries. Sensitization and activation of the trigeminal ganglia nerves that innervate the meningeal blood vessels is believed to play an important role in the initiation and maintenance of migraine pain. In this capacity, release of the neuropeptide calcitonin gene-related peptide (CGRP) and the resultant neurogenic inflammation is thought to underlie the pathophysiology of migraine. Largely due to the success of the serotonin Type 1 migraine drugs such as sumatriptan, migraine pathology and therapy has become a focus of intensive clinical and physiological research during the past decade. The effectiveness of these drugs is thought to be due to their ability to block the stimulated secretion of neuropeptides from trigeminal nerves to break the vicious nociceptive cycle of migraine. A component of this nociceptive cycle involves activation of mitogen-activated protein kinase signaling pathways. Indeed, activation of mitogen-activated protein kinase pathways can increase CGRP neuropeptide synthesis and secretion. Recently, the serotonin Type 1 agonists have been shown to cause a prolonged increase in intracellular Ca(2+) in trigeminal ganglia neurons and an increased phosphatase activity that can repress stimulated CGRP secretion and transcription. Identification of molecular signaling events in migraine pathology and therapy has provided new insight into the pharmacology and signaling mechanisms of sumatriptan and related drugs, and may provide the foundation for development of novel treatments for migraine.
Durham
Paul L
PL
Department of Biology, 225 Temple Hall, Southwest Missouri State University, Springfield, MO 65804, USA. pauldurham@smsu.edu
Russo
Andrew F
AF
D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008881:Migraine Disorders / Q000188:drug therapy* / Q000503:physiopathology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use*; D018170:Sumatriptan / Q000494:pharmacology / Q000627:therapeutic use; D014276:Trigeminal Nerve / Q000378:metabolism / Q000502:physiology
C470302:HTR1B protein, human; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D018170:Sumatriptan; D020928:Mitogen-Activated Protein Kinases; D015740:Calcitonin Gene-Related Peptide