Migraine patients are more sensitive to the immediate effects of GTN, in terms of headache and arterial dilatation, than healthy subjects and tension-type headache patients (97; see Chapter 23). Upon exposing migraine patients with and without aura to GTN, an immediate headache of mild to moderate intensity appeared during infusion. After a delay of around 1 hour, the patients experienced their usual premonitory symptoms; a characteristic migraine attack occurred 5 to 6 hours after GTN challenge (1,12,96,98). In only one patient with migraine with aura was an aura
triggered (1). Migraine attacks were induced in 75% of the migraine patients and were remarkably reproducible (1). A similar response was observed after sublingual administration of the long-acting nitrate isosorbide dinitrate (4). The surprisingly long latency period between GTN/histamine exposure and a fully developed migraine attack indicates that activation of NO—or steps in the NO-cGMP cascade—initiate a somewhat slow process that results in an attack. GTN-induced migraine can be attenuated by steroids, which inhibit iNOS, the enzyme responsible for slow inducible NO production (16), and partly prevented by 2 weeks of valproate treatment before GTN exposure (Fig. 30-2) (101). NO acts by increasing GMP. The cGMP-hydrolyzing phosphodiesterase 5 (PDE5) inhibitor sildenafil, which acts further along the NO-cGMP cascade exclusively by increasing cGMP, induced migraine in 10 of 12 patients with migraine without aura. No effects on the middle cerebral artery were detected (47). This study showed that NO itself is not necessary to induce migraine, but a cGMP-dependent mechanism without initial dilatation of the middle cerebral artery appear to be implicated. Others have shown that sildenafil increased endothelium-dependent flow-mediated vasodilatation (42). These results raise several questions. Is the headache caused by a direct effect on perivascular sensory nerve terminals? Is it a central effect? Why was dilatation based on the trigeminoparasympathetic reflex not observed?

Sicuteri et al. described first-degree relatives of migraine patients developing migraine after GTN, believing it only occurred in subjects with a genetic predisposition to migraine (91). Thus, migraine patients, and possibly first-degree relatives, are supersensitive to NO that initiates a process leading to a migraine attack (95). This appears
independent of the frequency of the patients’ naturally occurring migraine attacks (12).

Migraine patients showed no altered systemic endothelial response compared to controls (96), and the frequency of migraine attacks did not depend on the basal plasma NO levels (67). A mild parasympathetic dysfunction may be involved and may be responsible for the observed denervation supersensitivity to NO in cerebral arteries (97). A greater increase in cGMP after intramuscular injection of a cholinergic agent occurred in peripheral venous blood (68). This may provide a link between parasympathetic hypofunction and arterial NO hypersensitivity in migraine, because cholinergic agents seem to liberate NO, at least from the endothelium (24). Direct activation of perivascular sensory nerve fibers (65) or central effects of NO may be other possibilities.

The similar frequency for migraine in boys and girls before adolescence, increased frequency in women thereafter, and the importance of the menstrual cycle, indicate a possible role of the sex hormones for expression of migraine attacks; sensitivity to NO is greater with higher levels of estrogen (73).

CGRP also may play an important role in the pathogenesis of migraine via activation of CGRP receptors in the trigeminovascular system. The CGRP-receptor antagonist, BIBN4096BS, has proven efficacy in the acute treatment of migraine attacks and represents a new therapeutic principle (70). In migraine patients without aura, CGRP induced both an immediate and delayed headache with a similar time profile as after GTN and histamine infusion. The induced headaches were milder and the duration of the decreased velocity much shorter than after GTN (51). Interactions or cross-talk exist between NO and CGRP, but the mechanisms remain to be established. In some studies GTN/NO releases CGRP (8,45,92,105); in other studies CGRP activates NOS (7) although some studies show no interactions (20,35,54; see Chapter 16).

NO production may be elicited by pathologic reactions such as spreading depression of Leao, the proposed mechanisms of migraine aura (31,81). Increased levels of CGRP were measured during spontaneous migraine headache attacks (28). Sarchielli et al. measured CGRP, nitrites, cGMP, cyclic adenosine monophosphate (cAMP), neurokinin A (NKA), prostaglandin E₂ (PGE₂) and 6-keto PGF1α (the stable product of PGI2) in serial blood samples obtained from the internal jugular vein throughout a migraine attack (87). An immediate increase in nitrite, cGMP, CGRP, and NKA was observed to indicate activation of the NO and trigeminal systems. Two hours from attack onset PGE₂, 6-keto PGF1α, and cAMP also increased; a stress response was excluded. NO is involved in inflammation (22,86) and inhibition of platelet aggregation and adhesion (for review see Radomski et al. [78]). During migraine attacks, changes occur in NO of platelets (15,25,90), and serotonin and NO levels in monocytes (59,92). A rise excitatory amino acids was demonstrated in platelets and plasma (11,21,79), and total thiols were reduced (2).