Molecular mechanisms of antimigraine drugs: past, present, and future
© Springer-Verlag Italia 2004
Pharmacotherapeutic treatments for migraine have been documented for more than a century. Drugs that are effective in aborting an ongoing migraine attack exhibit a diversity of molecular mechanisms of action, but usually produce constriction of cranial arterial blood vessels, reversal of neurogenic inflammatory processes, and/or inhibition of sensory neuronal firing. This general understanding of drug action has led to the development of a unitary hypothesis for migraine pathophysiology, in which the onset of migraine is associated with activation of the trigemino-vascular system. Drugs which inhibit or reverse the activation of this system are effective acute treatments for migraine. Drugs useful in migraine prophylaxis have been discovered largely serendipitously, and display a fundamentally different pharmacology to the acutely effective agents. These drugs act at membrane receptors and ion channels, or by targeting intracellular biochemical pathways, and tend to reduce neuronal excitability in higher centers of the CNS. However, other than to suggest that this inhibits various migraine trigger events, it is not yet possible to delineate precisely how these drugs act to decrease the frequency and severity of migraine attacks. More recently, it has been observed that migraine is accompanied by sensory neuronal central sensitization that manifests as cutaneous allodynia in territory innervated by the trigeminal nerve. Although little is presently known about the ability of prophylactic drugs to modulate this process, it was recently shown that acute relief of migraine with triptan drugs is only reliably achieved when the drugs are given prior to the development of central sensitization. This important observation suggests that inhibition of migraine-related central sensitization could be an important new focus for future drug discovery, and may, for the first time, provide a rational target for the development of preventative medicines.