Pathophysiology of Migraine — New Insights

Abstract

Current theories propose that the primary dysfunction in migraine occurs within the CNS and that this evokes changes in blood vessels within pain-producing intracranial meningeal structures that give rise to headache pain. Migraine is now thought of as a neurovascular disorder. It has been proposed that genetic abnormalities may be responsible for altering the response threshold to migraine specific trigger factors in the brain of a migraineur compared to a normal individual. The exact nature of the central dysfunction that is produced in migraineurs is still not clear and may involve spreading depression-like phenomena and activation of brain stem monoaminergic nuclei that are part of the central autonomic, vascular and pain control centers. It is generally thought that local vasodilatation of intracranial extracerebral blood vessels and a consequent stimulation of surrounding trigeminal sensory nervous pain pathways is a key mechanism underlying the generation of headache pain associated with migraine. This activation of the ‘trigeminovascular system’ is thought to cause the release of vasoactive sensory neuropeptides, especially CGRP, that increase the pain response. The activated trigeminal nerves convey nociceptive information to central neurons in the brain stem trigeminal sensory nuclei that in turn relay the pain signals to higher centers where headache pain is perceived. It has been hypothesized that these central neurons may become sensitized as a migraine attack progresses. 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 that are expressed in human intracranial arteries and by inhibiting nociceptive transmission through an action at 5-HT1D receptors on peripheral trigeminal sensory nerve terminals in the meninges and central terminals in brain stem 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.

Trigeminal Nociceptive Transmission in Migraineurs Predicts Migraine Attacks

“…Although the pathophysiology of migraine is not yet fully understood, it has been postulated that peripheral events such as the activation of the trigeminovascular system lead to vasodilatation and plasma extravasation of meningeal vessels are most likely only a secondary event, as the origin of migraine attacks lies in the CNS (Goadsby, 2009). There are several brain structures that have been discussed as playing a crucial role in migraine disease (Hargreaves and Shepheard, 1999;May, 2009aMay, , 2009b. Migraineurs are characterized by an alteration of the interictal cortical excitability level, pointing to a deficit of filter mechanisms that is believed to protect individuals against sensory overload (Aurora et al, 2007;Coppola et al, 2007).…”

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

“…Sumatriptan has long been shown to reduce CGRP release concomitant with the relief of migraine pain and other primary headaches (Goadsby and Edvinsson, 1993). Triptans inhibit CGRP release by activating serotonin 5-HT 1D receptors located on trigeminal afferents, and they constrict meningeal arterial vessels by activating vascular 5-HT 1B receptors (Hargreaves and Shepheard, 1999). These effects are not exclusive for the trigeminovascular system but include, in particular, the coronary circulation.…”

Molecular cloning, sequence analysis and pharmacological properties of the porcine 5‐HT1D receptor

“…On the other hand, the trigeminal neural e ects of triptans seem to involve primarily the 5-HT 1D receptor, although 5-HT 1B and 5-ht 1F receptors have also been implicated Longmore et al, 1997;McCall, 1997;Wainscott et al, 1998;De Vries et al, 1999a;Hargreaves & Shepheard, 1999;Mitsikostas et al, 1999). The antimigraine e cacy of triptans has, therefore, been attributed to their ability to constrict large intracranial arteries and arteriovenous anastomoses via the 5-HT 1B receptor and to the inhibition of peripheral trigeminal sensory nerve terminals in the meninges and central terminals in brain stem sensory nuclei via the 5-HT 1D receptor (Hargreaves & Shepheard, 1999;Saxena & Tfelt-Hansen, 2000).…”