Headache is the most common reason for neurologic referral (10), and the majority of disabling headache has migraine as its biological basis. Migraine is certainly common (74), often very disabling (81), and increasingly recognized as a fundamentally neurologic disorder (49). Although many patients are now adequately treated with the therapies developed in the 1990s, there is still a substantial group of patients who continue to suffer and require better treatment (71). Here we try to capture possible approaches to both acute and preventive treatment of migraine that have emerged from laboratory science in the last decade. We have recently written on promising targets in other primary headaches (39). Here we cover targets for which there are clinical data to make some balance; elsewhere we cover targets promising because of effects on trigeminovascular nociceptive traffic, but without clinical data, such as the nociceptin (ORL-1) receptor, cannabinoid receptor, orexin receptors, and transient receptor potential (TRPV1 or VR-1) family receptor mechanisms, have been presented (38).

Although there are a range of acute and preventive therapies for migraine (71), serotonin 5-HT_1B/1D receptor agonists, triptans (36), stand out in terms of clinical and neuroscientific impact. The triptans are safe (18) and effective in migraine (27,28). However, the development of triptans left a so-called smoking gun by constricting vessels; did this mean migraine was after all a vascular disease, and could future developments disentangle the clinically undesirable, albeit small vascular risk penalty of triptans, and develop purely neurally acting medicines? Can the useful effects of 5-HT receptor agonism be dissected from the vascular complications?

The trigeminal innervation of the cranial circulation contains a number of neuropeptides, of which the most important for migraine seems to be calcitonin gene-related peptide (CGRP) (23). Stimulation of the trigeminal ganglion in cat and humans results in elevations in CGRP and substance P levels in the cranial circulation (46). However, during acute attacks of migraine (31,47), cluster headache (25,43), and paroxysmal hemicrania (45), CGRP is elevated but substance P is not. Similarly, nitroglycerin-induced migraine, which is very similar to the spontaneous attack (1,125), also exhibits increased levels of CGRP in plasma (64). Triptans inhibit CGRP release in the superior sagittal sinus of the rat (9) and in the spinal cord of the cat (5). Triptans inhibit release of CGRP into the cranial circulation of experimental animals when it is evoked by trigeminal ganglion activation (42,44). Similarly, stimulation of the superior sagittal sinus in cat leads to cranial release of CGRP (135), which can be blocked by triptans, but not by specific inhibits of neurogenic dural plasma protein extravasation (67,68). Interestingly, triptans also influence the CGRP promoter (21), and regulate CGRP secretion from neurons in culture (20). All of these data would predict that a CGRP receptor antagonist would have antimigraine effects and not need have vascular actions.

Successful treatment of acute migraine (42) or cluster headache (25,43) with sumatriptan normalizes cranial CGRP levels. Moreover, local microiontophoresis of the CGRP-receptor antagonist BIBN4096BS (19,85) inhibits trigeminocervical neurons (121). This potent CGRP-receptor antagonist has been shown to be effective in the treatment of acute migraine (86) and is devoid of vasoconstrictor actions in humans (92,93). CGRP antagonists may have a preventive as well as acute attack effects that merits consideration and eventual study. They hold great promise for both migraine and cluster headaches.

Glutamate is the major excitatory neurotransmitter and plays an important role in conveying sensory and nociceptive information in the brain and spinal cord. It acts through both ionotropic (ion channel-type) and G-protein-coupled (metabotrophic) receptor families. Glutamatelike immunoreactivity has been seen in tooth pulp neurons that project to the trigeminal nucleus caudalis in the rat (13); glutaminase immunoreactivity is most dense in the nucleus caudalis when compared with other parts of the trigeminal nucleus of the rat (76). Each of N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), kainite, and metabotropic glutamate receptors have been identified in the superficial laminae of the trigeminal nucleus caudalis of the rat (124). Ionotropic receptor channel blockers, such as MK-801 acting at the NMDA receptor, and GYKI-52466, acting at the AMPA receptor, have been found to block trigeminovascular nociceptive transmission in the trigeminocervical nucleus (12,40,122). Similarly, both NMDA and non-NMDA ionotropic receptor blockades reduces fos protein expression in trigeminal nucleus caudalis associated with intracisternal capsaicin injection (83,84). Last, glutamate receptors are involved in transmission of trigeminovascular nociceptive information in the ventrobasal thalamus (115). This glutamate-mediated thalamocortical transmission, which must be crucial in the appreciation of head pain, can be modified by β-adrenoceptor antagonists effective in migraine, such as propranolol, by a β₁-mechanism (99,114).

Consistent with these preclinical data there are small trials that suggest glutamate blockade as a strategy to treat migraine. A mixed AMPA/kainate receptor antagonist, LY293558, when given by intravenous injection, was shown to be effective and well tolerated in acute migraine (105). Interestingly, ketamine, which acts at the glutamate NMDA receptor, reduced aura symptoms in patients with familial hemiplegic migraine in an open-label study (65). Taken together these data speak to a high likelihood that glutamate receptor antagonists would have effects in both migraine and cluster headaches.

Much has been written of nitric oxide (NO) and migraine, and this review cannot hope to do this area justice (87,126,127). Moreover, NO donors are clearly effective triggers of acute cluster headache (24). Some important mechanistic data in migraine are cited here because they bear on the issue of nonvascular therapeutic development. It has been considered that nitroglycerin triggers migraine, or indeed cluster headache, by a necessary dilation of cranial vessels (62). However, three recent observations suggest that dilation is an epiphenomenon. First, nitroglycerin triggers premonitory
symptoms in many patients (1). These were no different to those reported in spontaneous attacks (35) and occurred well after any vascular change would have been present. Second, downstream activation of the cyclic guanosine monophosphate pathway by sildenafil can induce migraine without any change in middle cerebral artery diameter (70). Third, dilation of the internal carotid artery after nitroglycerin administration in cluster headache patients is dissociated in time from the onset of the attack (79). Taken together these observations suggest that although 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 example, of inducible NO synthase has been suggested (102), or in inhibition of trigeminocervical complex fos expression with NO synthase blockade has also been reported (58). 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 both migraine and cluster headaches.