New Research Areas

Serotonin 5HT1B/1D receptor agonists, the triptans 7, and related 5HT receptor agonists, 9, 10, provided the most important advance in migraine therapeutics in the four millennia that the condition has been recognized. Simultaneously the development of triptans, with their vasoconstrictor action, produced a small clinical penalty in terms of coronary vasoconstriction and an enormous intellectual question: the extent to which migraine is a vascular problem. Functional neuroimaging and neurophysiological studies have consistently developed the theme of migraine as a brain disorder and thus demand that the search for neurally acting antimigraine drugs should be undertaken. CGRP receptor blockade is an effective acute antimigraine strategy and is nonvasconstrictor terms of the mechanism of action. It is likely that direct blockade of CGRP release by inhibition of trigeminal nerves would be similarly effective. Options for such an action based on preclinical work include: serotonin 5HT1F and 5HT1D receptor agonists, glutamate excitatory amino acid receptor antagonists, adenosine A1 receptor agonists, nociceptin, vanilloid TRPV1 receptors, cannabinoid CB1 receptors, orexin receptors, and nitric oxide (NO) mechanisms.49 Those mechanisms tested in patients are discussed below. Adenosine A1 receptor agonists were discussed above. 5HT1F Receptor Agonists

The potent specific 5HT1F agonist LY-334370 blocks neurogenic plasma protein extravasation.67 LY-334370 10 is effective in acute migraine, albeit at doses with some central nervous system side effects and no cardiovascular problems.68 Unfortunately, development was stopped because of a nonhuman toxicity problem. 5HT1F receptor activation is inhibitory in the trigeminal nucleus in rat and cat, albeit in cat seeming less potent than 5HT1B or 5HT1D receptor activation.68 There is a good expectation that 5HT1F receptor agonists would be both nonvascular and probably useful in migraine and cluster headache. 5HT1D Receptors

5HT1D receptor agonists are potent inhibitors of neurogenic dural plasma protein extravasation70 and have no vascular effects. Peptidergic nociceptors express these receptors in a manner that is activation-dependent.71 Specific potent 5HT1D agonists have been developed by taking advantage of similarities between human and nonhuman primate 5HT1B and 5HT1D receptors. PNU-142633 9 was clinically ineffective,72 although it was a relatively weak agonist when compared to sumatriptan in in vitro studies,73 and was poorly brain-penetrant. Since this NCE was developed using gorilla receptors, there are questions as to whether this was the correct compound to test the 5HT1D hypothesis. Preclinical studies are able to dissect out a potent 5HT1D receptor-mediated inhibition of the trigeminocervical complex,69 so that this mechanism remains both plausible and not fully tested. Nitric Oxide Synthase Inhibitors

Much has been written of NO and migraine.51 Nitroglycerin triggers migraine by a necessary dilation of cranial vessels. However, three recent observations suggest that dilation is an epiphenomenon. First, nitroglycerin triggers premonitory symptoms in many patients.74 These were no different to those reported in spontaneous attacks52 and occurred well after any vascular change would have been present. Secondly, downstream activation of the cyclic guanosine monophosphate pathway by sildenafil can induce migraine without any change in middle cerebral artery diameter.75 Thirdly, dilation of the internal carotid artery after nitroglycerin administration in cluster headache patients is dissociated in time from the onset of the attack.76 Together these observations suggest that, while NO mechanisms may play a role in some part of the pathophysiology of these disorders, it need not be a vascular effect. A role for inducible NO synthase has been suggested,77 and inhibition of trigeminocervical complex fos expression occurs with NO synthase blockade.78 Both examples provide a nonvascular approach, although potentially with rather different NO synthase subtype targets. The available data, therefore, suggest that NO-based developments may find clinical utility in migraine, and indeed the initial clinical study was positive.79

The prospect of a nonvasconstrictor acute migraine therapy offers a real opportunity to patients, and perhaps more importantly, provides a therapeutic rationale to plant migraine firmly in the brain as a neurological problem, where it undoubtedly belongs.

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Headache Happiness

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