Pathophysiology of migraine - New insights

Current theories propose that the primary dysfunction in migraine occurs wi thin the CNS and that this evokes changes in blood vessels within pain-prod ucing intracranial meningeal structures that give rise to headache pain. Mi graine is now thought of as a neurovascular disorder. It has been proposed that genetic abnormalities may be responsible for altering the response thr eshold to migraine specific trigger factors in the brain of a migraineur co mpared to a normal individual. The exact nature of the central dysfunction that is produced in migraineurs is still not clear and may involve spreadin g depression-like phenomena and activation of brain stem monoaminergic nucl ei that are part of the central autonomic, vascular and pain control center s. It is generally thought that local vasodilatation of intracranial extrac erebral blood vessels and a consequent stimulation of surrounding trigemina l sensory nervous pain pathways is a key mechanism underlying the generatio n of headache pain associated with migraine. This activation of the 'trigem inovascular system' is thought to cause the release of vasoactive sensory n europeptides, especially CGRP, that increase the pain response. The activat ed trigeminal nerves convey nociceptive information to central neurons in t he brain stem trigeminal sensory nuclei that in turn relay the pain signals to higher centers where headache pain is perceived. It has been hypothesiz ed that these central neurons may become sensitized as a migraine attack pr ogresses. The 'triptan' anti-migraine agents (e.g. sumatriptan, rizatriptan , zolmitriptan naratriptan) are serotonergic agonists that have been shown to act selectively by causing vasoconstriction through 5-HT1B receptors tha t are expressed in human intracranial arteries and by inhibiting nociceptiv e transmission through an action at 5-HT1D receptors on peripheral trigemin al sensory nerve terminals in the meninges and central terminals in brain s tem sensory nuclei. These three complementary sites of action underlie the clinical effectiveness of the 5-HT1B/1D agonists against migraine headache pain and its associated symptoms.