Migraine pain: reflections against vasodilatation

The first is not a question but an observation: looking at the photograph of the 25 key opinion leaders reunited in the Leeds Castle meeting of 1995 to discuss the sumatriptan mechanism, surprisingly Prof Sicuteri is absent, the scientist of the 5-hydroxytryptamine (5-HT) central theory of migraine, which shows for the first time an alteration of 5-HT metabolism in migraine, which introduces methysergide in the prevention of migraine, which shows that methysergide have 5-HT agonistic activity in man, that is findings leading to the idea that serotonin might have pathophysiological involvement in migraine.

The second concerns the statement that sumatriptan, differently from newer triptans, does not normally act centrally because it does not pass the blood brain barrier. Independently from any animal studies, it was evident to clinicians, from the early use of subcutaneous sumatriptan, that this drug provoked in some cases side effects such as dysphoria, sedation, drowsiness, depression, etc., which were clearly central in origin [14‐16].

The third concerns the Humphrey’s statement that he had developed sumatriptan by observation of the studies reporting that ergotamine, 5-HT and also methysergide had beneficial effect in migraine attack probably acting as vasoconstrictors of cephalic vessels. The beneficial effect of 5-HT in migraine attack is, however, uncertain, and also migraine provocation was reported [see 17]. He therefore developed an analogue of 5-HT with selective vasoconstriction on cephalic vessels through 5-HT₁ receptor subtype, and this was their idea of sumatriptan action. This led to the so-called “triptan revolution” within the pharmaceutical industry and the availability of at least seven triptans in the market place today. Unfortunately, this revolution was not sustained by the population given the low utilization of triptan in the world [18]. However, we have had the pleasure of reading in the Humphrey’s paper [10]: “My favourite notion is that central sensitization may arise from a disorder of descending inhibition, which would actually fit with the idea of a hypothetical migraine generator or something that is abnormal in the brain. Also, if there is altered withdrawal of descending inhibition unilaterally, it would explain why there is hemicrania”. Therefore, Humphrey today, even though he sustained that painful impulses do originate peripherally from cephalic vessels and that sumatriptan acts almost entirely peripherally [19], moves his attention towards the brain!

Selective and potent inhibitors of PPE in animal models were ineffective in the acute treatment of migraine [see 21, 22].

Selective agonists of presynaptic 5-HT_1D receptors (which would blocks SP release from peripheral trigeminal sensory endings) were ineffective in migraine attack, and there was no correlation between the potency on PPE and antimigraine activity [see 5, 21, 22]. These observations reinforce the view that the antimigraine activity of triptans is dependent upon their interaction with the 5-HT_1B receptors, that is through the vasoconstriction.

Frequently the doses of antimigraine agents employed in animal studies are higher than the clinical one. Recording the history of ergotamine and dihydroergotamine in migraine, Tfelt-Hansen cited the original study of Moskowitz [23], and affirms that in rats, i.v. ergotamine in doses similar to those used to treat migraine attack and cluster headache, inhibit PPE within the dura mater [24]. The therapeutic i.v. or i.m. doses of ergotamine in migraine is 250 μg (about 2.5–5 μg/kg). The ergotamine doses employed in NI studies was 50 μg/kg [20], that is doses at least ten times higher. Sumatriptan inhibits the release of CGRP from cultured trigeminal neurons but the concentration required was higher than the estimated plasma concentrations in patients receiving the drug for migraine [9].

The site of triptans antimigraine action was suggested to be in all the stations of the nociceptive trigeminal pathway, starting from meningeal vessel to the thalamus, that is rostral relay of nociceptive trigeminal information [5, 10, 19, 25, 26]. However, some evidence shows that neither peripheral nor central trigeminovascular neurons are directly inhibited by sumatriptan. Rather the triptans action appears to be exerted through presynaptic 5-HT_1B/1D receptors in the dorsal horn to block synaptic transmission between axon terminal of the peripheral trigeminovascular neurons and cell bodies of their central counterparts (trigeminal nucleus caudalis) [27, 28]. The last findings support that the vasoconstrictive effects of sumatriptan and its inhibition of PPE does not play a significant role in the termination of migraine pain. The 5-HT_1D receptors are localized in fact in trigeminal primary afferent nociceptors, in dense core vescicles, which suggests that they would be available for interaction with triptan only with nociceptive stimulation of sufficient intensity [29]. Triptan receptors are found equally among trigeminal sensory afferents and afferents which innervate the rest of the body [29]. This is at odds with the prevailing view that triptans have selective actions for migraine/cephalic pain. However, there are also studies showing a central antinociceptive effect of triptans. Triptan microinjected in the ventrolateral periaqueductal gray inhibit (probably activating descending pain-modulating pathways) dural, but not facial and corneal nociceptive input [30]. More recently a profound anti-hyperalgesic action of small intrathecal doses, but not 200-fold greater systemic doses, of sumatriptan was found in experimental inflammation in non-cephalic regions [31]. Sumatriptan inhibition of non-trigeminal pain condition involving NI was also described [32]. Data from microinjection studies also suggest that sumatriptan may act within the rostroventral medulla (RVM) to attenuate visceral pain through activation of 5-HT_1B receptors [33].

Sumatriptan has no inhibitory effect on the discharge of dural nociceptors, but produces a transient discharge of these neurons [28]. This excitatory effect might underlie the initial worsening of headache which was reported after triptan administration [15, 17, 34‐36]. It was suggested that this initial headache exacerbation was due to relatively low levels of triptan entering the circulation shortly after administration which activates meningeal nociceptors [34]. It was also sustained that it may simply due to vasodilator effects that occur at lower concentrations than their vasoconstrictor activity as a result of sympathoinhibition [5]. However, small intravenous bolus doses of sumatriptan (500 μg) or ergotamine (50 μg) provoke a sudden headache exacerbation which is more convincingly due to transitory high blood levels than low levels [17, 36]. Moreover, the 5-HT doses (4-40 mg) utilized in studies showing migraine provocation [37] seem higher that the ones (2–7.5 mg) utilized in studies showing beneficial effect [38, 39]. Also the superior efficacy of subcutaneous triptans in comparison to the oral form was attributed to the rapid rise in plasma levels (T_max was 10 min) [40].

A substantial increase of CGRP levels in jugular vein but not in peripheral vein in migraine attack [43]. Even in nitroglycerin (NTG)-induced migraine attack an increase of plasma CGRP was found, but not in immediate headache or in subjects without migraine attack [44].

The CGRP infusion (2 μg/min/20 min) provokes in migraine subjects immediate and delayed (1–12 h, median 5) headache, sometimes with migraine-like characteristics, with similar latency but lesser intensity than that provoked by glyceryl trinitrate (GTN) and histamine. It was argued that nitric oxide (NO) may be a common mediator of GTN, histamine and CGRP-induced headache; otherwise, CGRP may be the common mediator of GTN, histamine and CGRP [45].

The CGRP receptors antagonists were effective in migraine attack with efficacy comparable to triptans [46, 47].

Using an intra-patient comparison design, CGRP was not found to increase in external jugular vein and in peripheral vein during migraine attack in comparison to attack-free period [48]. Previous studies compared CGRP blood levels during attack with those of control subjects, and the results can be affected by a large inter-individual variation of CGRP levels.

The CGRP infusion (1.5 μg/min/20 min) in healthy subjects induces mild immediate and delayed headache, and dilatation of middle cerebral artery (MCA) and of superficial temporal artery (STA). The CGRP antagonist olcegepant prevents the headache and STA dilatation, but not that of MCA, suggesting a extracerebral action. However, at the end of infusion, the CGRP plasma concentration was increased 4–5 times from baseline, and is higher than that found in spontaneous migraine attack [49].

There were no differences in the degree of vasodilatation of MCA (moreover mild) and of peripheral arteries between migraine and healthy subjects [50‐52].

There were no differences in immediate and delayed headache (of mild intensity and low frequency) and in the degree of MCA and STA vasodilatation between familial hemiplegic migraine and healthy subjects [53].

Recently, with sensitive and non-invasive magnetic resonance angiography (3T MRA), it was shown that during migraine induced by NTG, the diameter of intracerebral (internal carotid, middle and posterior cerebral, basilar) and extracerebral (mean meningeal, external carotid) arteries were not different from baseline, and there was no difference between headache and non-headache sides. Moreover, there was no change in basilar and internal carotid artery blood flow during NTG infusion or migraine. These findings suggest that migraine attack is not associated with vasodilatation of cerebral or meningeal vessels [54].

Many studies show that different vasoactive neurotransmitters found in perivascular nerve fibres and other vasodilating agents may trigger headache, but with some contradictions (Table 1). The immediate dilatation of the MCA seen after treatment with GTN, histamine, CGRP, dipyridamole, has been considered to play a causative role in the induction of migraine attacks [55, 56]. Dipyridamole and CGRP (both cAMP-elevating compounds) induce migraine less frequently than GTN and sildenafil [45, 55, 56, 58, 59]. However sildenafil, which is more effective migraine inducing agent than CGRP and probably also than histamine, does not induce cephalic vasodilatation [58]. It was suggested that parasympathetic nervous system may be involved in the initiation and maintenance of migraine attacks [67]. However, vasoactive intestinal peptide (VIP), a neurotransmitter of cerebral parasympathetic perivascular nerve fibres, provokes marked cephalic vasodilatation but not migraine, providing further evidence against a purely vascular origin of migraine [62]. Even the moderate degree of dilation after cilostazol or dipyridamole makes a simple mechanical dilation an unlikely source of pain [60, 61]. Thus the dilatation of cephalic arteries seems unlikely to be the direct cause of the migraine-like attacks occurring hours after the infusion of vasodilator drugs.

Sumatriptan inhibits CGRP release from stimulated trigeminal neurons but not in baseline conditions [9, 68]. Animal studies show that sumatriptan does not inhibit CGRP vasodilatation [32, 69, 70]. Neither dural nor systemic administration of CGRP, at doses that evoked dural vasodilatation, had a detectable effect on discharge of dural nociceptors, which are also subjected to rapid desensitization [28]. Other evidence for a possible weak action on CGRP in the periphery are the brief (7–10 min) plasma half-life of GGRP in humans [21] and tachyphylaxis of the vascular responses [71]. Even the excitation of trigeminal brainstem neurons by the application in the meningeal subarachnoid space of a mixture of inflammatory mediators was subjected to tachyphylaxis [72].