Ligandy receptorów serotoninowych w terapii migreny
Serotonin receptor ligands in migraine therapy
Migraine is a common, chronic disorder affecting the lives of millions of people worldwide. It is characterized by a throbbing headache, which is usualy unilateral, and is often associated with nausea, vomiting, photophobia and phonophobia. The precise mechanisms underlying the cause of migraine are still unclear and several theories regarding its etiology have been proposed. The vasodilatory theory of migraine suggested that extracranial arterial dilatation during an attack was related to migraine pain; the neurological theory propossed that migraine resulted from abnormal firing in brain neurons. The neorogenic dural inflammation theory supposed thet the dural membrane surrounding the brain become inflammed and hypersensitive due to release of neuropeptides from primary sensory nerve terminals. Substantia P, calcitonin gene-related peptide (CGRP) and nitric oxide are all thought to play a role in the dural inflammation cascade. Several clinical and experimental observations confirm that serotonin (5-hydroxytryptamine, 5-HT) has an important role in producing or maintaining migraine attack. The serotonin connection with migraine is additionally supported by the efficacy of serotonin receptor ligands. Sumatriptan - designed to interact with the specific type of serotonin receptors - was the first drug marketed worldwide for acute treatment of migraine. It activates 5-HT1B/1Dserotonin receptors on nerves and blood vessels and in so doing turns off inflammation and shrinks swollen blood vessels, believed to contribute to migraine pain. The introduction and the success of sumatriptan initiated an intense search for improved triptamide derivatives. New medications are being released in rapid sequence. Today four second-generation triptans are on the market: zolmitriptan, naratriptan, rizatriptan and almotriptan and two others (eletriptan and frovatriptan) are about to be marketed. All of the triptans share a common mode of action, but the new ones are more lipophilic and have higher oral bioavailability than sumatriptan. Adverse events for triptans include: tightening, flushing and paraesthesias of unknown case. All of them cause narrowing of arteries, including coronary arteries, and although serious adverse vascular events are very rare, triptan use is contraindicated in patients with vascular disease. Finally, a problem with the triptans is a recurrence of headache a few hours after initial successful treatment. Because clinical-trial data suggest that the differences among the various triptans are subtle rather than dramatic, it is not yet clearly established whether these new agents represent a major improvement over sumatriptan in therapeutic effectiveness. Despite an indisputable progress in migraine therapy triptans have not yet provided an optimal answer and future work in this field is still warranted. Recently, a novel arylpiperazine derivative of serotonin with potent, selective and unique high intrisic activity at 5-HT1B/1D receptors (F 11356) is developed to be superior over the representatives of triptans family. Apart from the 5-HT1B/1D agonists several other classes of ligands have been suggested as potentially beneficial in acute treatment of migraine, namely 5-HT1F agonists and 5-HT2H antagonist. These new directions as well as a review of a currently available antimigraine drugs from the family of 5-HT receptor ligands are summarized in this article.
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