Headache Phase Of Migraine Research Articles

Patterns of fos expression in the rostral medulla and caudal pons evoked by noxious craniovascular stimulation and periaqueductal gray stimulation in the cat

Functional imaging studies and clinical evidence suggest that structures in the brainstem contribute to migraine pathophysiology with a strong association between the brainstem areas, such as periaqueductal gray (PAG), and the headache phase of migraine. Stimulation of the superior sagittal sinus (SSS) in humans evokes head pain. Second-order neurons in the trigeminal nucleus that are activated by SSS stimulation can be inhibited by PAG stimulation. The present study was undertaken to identify pontine and medullary structures that respond to noxious stimulation of the superior sagittal sinus or to ventrolateral PAG stimulation. The distribution of neurons expressing the protein product (fos) of the c-fos immediate early gene were examined in the rostral medulla and caudal pons of the cat after (i) sham, (ii) stimulation of the superior sagittal sinus, (iii) stimulation of the superior sagittal sinus with PAG stimulation, or (iv) stimulation of the PAG alone. The structures examined for fos were the trigeminal nucleus, infratrigeminal nucleus, reticular nuclei, nucleus raphe magnus, pontine blink premotor area, and superior salivatory nucleus. Compared with all other interventions, fos expression was significantly greater in the trigeminal nucleus and superior salivatory nucleus after SSS stimulation. After PAG with SSS stimulation, on the side ipsilateral to the site of PAG stimulation, fos was significantly greater in the nucleus raphe magnus. These structures are likely to be involved in the neurobiology of migraine.

A delayed class of BOLD waveforms associated with spreading depression in the feline cerebral cortex can be detected and characterised using independent component analysis (ICA).

An application of independent component analysis to blood oxygenation level- dependent MRI (BOLD-MRI) results was used to detect cerebrovascular changes that followed the initiation of cortical spreading depression (CSD) in feline brain. The cortical images were obtained from a horizontal plane at 28 s intervals before, and for 1.4-1.75 h after, KCl dissolved in agar (KCl/agar) had been directly applied to the left suprasylvian gyrus of 13 anesthetized cats for 10 min. It successfully resolved, for the first time, a novel class of prolonged, and delayed, biphasic BOLD waveforms. These were larger in amplitude ( approximately 20%), longer lasting and more delayed in onset (13-33 min) than the brief propagating (90 s) BOLD increase ( approximately 4%) already known to be associated with CSD on earlier occasions. Furthermore, such changes occurred in localized regions on the hemisphere ipsilateral to the site of stimulus application in 4 out of 5 control subjects rather than themselves generating propagating waves. Finally, the biphasic waveforms were consistently abolished in the 4 experimental animals studied following the i.v. administration of sumatriptan (0.3 mg kg(-1)), an antimigraine 5-HT(1B/1D) agonist, 15 min before the application of the transient stimulus. They were abolished in 2 out of 4 animals following the intraperitoneal (i.p.) administration of SB-220453 (tonabersat: 10 mg kg(-1), 90 min before stimulus application), a novel anticonvulsant that has recently been reported to inhibit CSD. ICA has thus been successful in detecting a novel localized, as opposed to propagating, signal of potential physiological significance hidden in complex BOLD- MRI data, whose sensitivity to sumatriptan may relate it to the cerebrovascular changes reported in the headache phase of migraine.

Prostaglandin E2 injected into the posterior hypothalamus has no effect on trigeminal nociception in the rat

Craniovascular prostaglandin E2 (PGE2) release is elevated in the headache phase of migraine and in experimental models of headache. PGE2 synthesised in the brain may be involved in modulating trigeminal nociception. We examined whether PGE2 injected into the posterior hypothalamus could modulate trigeminovascular nociception. In seven rats, electrophysiological recordings were made from trigeminal nucleus caudalis neurons responsive to noxious middle meningeal artery stimulation and inhibited by bicuculline activation of the posterior hypothalamus. Microinjection into the posterior hypothalamus of a non-pyrogenic dose of PGE2 (2.5 μg/ml) produced no effect on nociceptive trigeminal nucleus caudalis neurons compared with saline injection ( P=0.29). The mean response to PGE2 injection was 97% of baseline. We conclude that PGE2 in the posterior hypothalamus is unlikely to play a significant role in modulating trigeminal nociception.

A prospective study of the headache phase in 32 migraine with aura patients.

For an accurate description of the clinical features of the headache phase in migraine with aura (MA) attacks, we thought it useful to conduct a prospective study of consecutively referred MA patients seeking treatment at the Headache Centre of the University of Parma Institute of Neurology. The case series included 32 patients (22 women and 10 men). At the time of the first visit, each patient was given a questionnaire to be filled in at the next MA attack. Six patients (four women and two men) had attacks of migraine aura without headache. Among the remaining 26 patients (18 women and eight men), the duration of the headache phase was <24 h in 23 (88.5%); pain location was bilateral in 14 (53.8%) and unilateral in 12, but occurring on the opposite side to aura only in one patient; pain intensity was mild or moderate in 13 (50.0%). The headache phase of MA appeared to have clinical features that differed widely from patient to patient and was consistent with the International Headache Society diagnostic criteria for migraine without aura in 26.9% of patients and for tension-type headache (TTH) in 23.1%.

4991W93 inhibits release of calcitonin gene-related peptide in the cat but only at doses with 5HT 1B/1D receptor agonist activity?

Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. CGRP may have a role in migraine through its potent cranial vasodilator effects, or by an action on trigeminal nerve activity, both of which are targeted by 5HT 1B/1D agonist drugs. CP122,288, a conformationally restricted analogue of sumatriptan that is a potent inhibitor of neurogenic plasma protein extravasation (PPE), was ineffective at inhibiting CGRP release at a single low dose; and is also ineffective as an acute anti-migraine compound. However, it remained unclear as to whether, as a class, the conformationally-restricted triptan analogues could have inhibitory effects on CGRP in higher doses. 4991W93, a conformationally restricted analogue of zolmitriptan, is also a potent inhibitor of PPE at doses without 5HT 1B/1D-mediated effects, that was developed as an anti-migraine drug, and thus was suitable to test whether higher doses of such conformationally restricted triptan analogues could inhibit trigeminal-evoked CGRP release. The superior sagittal sinus (SSS) was stimulated in 14 anaesthetised cats and external jugular vein blood samples were analysed by radioimmunoassay for CGRP levels before, 1 min after SSS stimulation, and 1 min after SSS stimulation in the presence of 4991W93. Stimulation of the SSS resulted in release of CGRP from the external jugular vein. 4991W93 at a dose of 0.1 and 10 μg/kg, selected for maximal PPE blocking effects in rodents, was ineffective at inhibiting CGRP release, with an SSS stimulation level of 78±4 pmol/l compared to a post-4991W93 level of 79±3 pmol/l ( n=4). In comparison CGRP release was inhibited after a dose of 100 μg/kg 4991W93 from 64±6 to 36±3 pmol/l ( n=5). Given that 4991W93 is inactive clinically at non-vascular doses, it seems clear that the 5HT 1B/1D agonist effects of the compound are necessary for blockade of CGRP release and thus any anti-migraine action. Taken with the clinical results, these data emphasise the importance of CGRP release in migraine, and suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.

Blockade of calcitonin gene-related peptide release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122,288

The pathophysiological basis for the pain of migraine has been the subject of substantial attention and must include activation of elements of the trigeminal innervation of the cranial vessels, the trigeminovascular system. Recently, consideration of trigeminal-evoked neurogenic plasma protein extravasation (PPE) as a model for the pain has driven the search for compounds with specific anti-extravasation properties. Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. CGRP may have a role in migraine through its potent cranial vasodilator effects or by an action on trigeminal nerve activity, both of which are targeted by 5HT1B/1Dagonist drugs but does not itself produce PPE. It has been suggested that 5HT1B/1Dagonists may have an anti-migraine effect via inhibition of PPE in the dura mater. Avitriptan and CP122,288 both have strong binding affinities for 5HT1B/1Dreceptors, but only CP122,288 is a potent inhibitor of PPE. In this study we sought to compare the effects of CP122,288 and avitriptan on jugular vein CGRP release after stimulation of the superior sagittal sinus (SSS) in the cat. In eleven anaesthetized cats external jugular vein blood samples were analyzed by radioimmunoassay for CGRP levels in three settings: a) control, b) 1 min after SSS stimulation and c) 1 min after SSS stimulation in presence of drug. Stimulation of the SSS resulted in release of CGRP from the external jugular vein (77±1 pmol/L). At a PPE-inhibitory dose in rat (100 ng/kg intravenously) CP122, 288 had no effect on CGRP release (77±6 pmol/L) whereas at a clinically relevant dose (50 μg/kg intravenously) avitriptan blocked CGRP release. This study demonstrates that the potent inhibitor of PPE, CP122, 288, which has been shown in clinical trials to be ineffective in treating acute migraine attacks, had no effect on CGRP release, whereas the effective anti-migraine drug and relatively impotent inhibitor of PPE, avitriptan, blocked CGRP release. These data emphasize the importance of CGRP release and its possible independence from PPE in migraine and more importantly suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.

Potential Neurogenic and Vascular Roles of Nitric Oxide in Migraine Headache and Aura

It has long been known that nitrate and nitrite medications consistently cause significant headache as a side effect. Classical research has shown that cerebral vasodilation accompanies the use of these medications. More modern studies suggest that these vasodilators exert their action on blood vessels via nitric oxide and its second messenger, cyclic guanosine monophosphate. This paper reviews research studies and theoretical articles which address the concept that nitric oxide plays a major role in the vasodilation associated with the headache phase of migraine with aura. A brief discussion of nitric oxide biochemistry and pharmacology follows. In addition, there is a review of evidence examining the possible contributions of nitric oxide to the neurogenic and vascular events associated with spreading cortical depression, an animal model of migraine aura. The paradoxical hypotheses that nitric oxide may contribute to both the propagation of spreading cortical depression and its limitation are presented. Finally, a rationale for the experimental use of nitric oxide agonists and antagonists in the abortion of migraine aura is introduced.

Blink Reflex in Migraine and Tension‐Type Headache

The blink reflex was studied in 19 patients with migraine, 10 patients with tension-type headache, and 30 healthy controls. Significantly lower values of R2 and R2' amplitude and size were found in the migraine group, compared with the healthy control group. The differences were independent of the stimulation side (headache or nonheadache) and highly significant (P<0.001). The abnormalities of R2 and R2' amplitude and size were found only during the headache phase of migraine, being normal between migraine attacks. R1 latency and amplitude were normal in all patients. The blink reflex was normal in all the patients with tension-type headache. Subcutaneous injection of sumatriptan in 10 of the 19 migraineurs, during the headache phase, restored R2 and R2' amplitude and size values to normal. Our findings indicate that the brain stem interneuron part of the blink reflex arc may be diffusely suppressed in migraine, only during the headache phase. Furthermore, blink reflex may be an objective laboratory method to monitor the effectiveness of specific drugs proposed for the treatment of migraine.

Porcine carotid vascular effects of eletriptan (UK-116,044): a new 5-HT1B/1D receptor agonist with anti-migraine activity.

It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine. Indeed, a number of acutely acting anti-migraine drugs, including the ergot alkaloids and sumatriptan, constrict porcine carotid arteriovenous anastomoses. In this study, using pentobarbital anaesthetised pigs, we investigated the effects of eletriptan, a close structural analogue of sumatriptan, on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient (capillary) fractions. Eletriptan (10, 30, 100, 300 and 1000 microg kg(-1), i.v.) decreased the total carotid blood flow, exclusively by decreasing cephalic arteriovenous anastomotic blood flow; nutrient blood flow, particularly to the ear, skin and fat, was significantly increased. The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50% (ED50) were, respectively, 117+/-21 microg kg(-1) (251+/-45 nmol kg(-1)) and 184+/-42 microg kg(-1) (396+/-91 nmol kg(-1)); the highest dose caused reductions of 84+/-3% and 77+/-4%, respectively. The eletriptan-induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective 5-HT1B/1D receptor antagonist GR127935 (0.5 mg kg(-1)). On the basis of these results, we conclude that (1) the eletriptan-induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by 5-HT1B/1D receptors, and (2) eletriptan should be effective in aborting migraine headache. Clinical studies have already demonstrated its therapeutic action in migraine patients.

Migraine Postdromes: Symptoms After Attacks

To determine the nature and duration of symptoms after the headache phase of migraine, 40 migraineurs (11 with and 29 without an aura) were given a questionnaire to complete on the day after a migraine attack. The most common symptoms that remained were physical and mental tiredness, subdued or depressed mood, impaired concentration, reduced physical activities and yawning; weak or clumsy limbs, head tenderness, neck ache or stiffness, impaired sight and altered fluid balance were less frequent. The number of symptoms ranged from 2 to 11 (average 6) per patient lasting for a mean of 18 h, usually the whole of the next day. Symptoms after the main migraine attack can help to diagnose migraine particularly when there is no aura before the onset of headache. Eliciting postdromes aids patient-doctor rapport and confidence. The range of symptoms lends support to the notion that the whole of the brain is involved in the aftermath of migraine attacks.

The 21-aminosteroid antioxidant tirilazad mesylate, U-74006F, blocks cortical hypoperfusion following spreading depression

Cortical spreading depression (SD) has been implicated in the pathophysiology of classical migraine headache and cerebral ischemia. A reduction in cerebral blood flow (CBF), mimicking that seen during the aura and headache phase of migraine, is typically observed following SD in the rat. This phenomenon may also play a role in potentiating ischemic brain damage. In the present study, brief cortical exposure to 1 M KCl produced a marked suppression of EEG amplitude which persisted 20 min in the rat. Upon normalization of the EEG, cortical blood flow declined 20–30% and remained low for at least 2 h. Treatment with a 1 mg/kg i.v. dose of the 21-aminosteroid antioxidant trilazad mesylate (U-74006F), 2 min following KCl application, completely blocked the hypoperfusion while leaving the magnitude and duration of the EEG suppression and mean arterial pressure unchanged. Tirilazad mesylate is a potent inhibitor of oxygen radical-mediated lipid peroxidation both in vitro and in vivo. Thus, based on present results, an oxygen radical hypothesis is proposed to account for the SD-induced cerebral hypoperfusion.

The role of adenosine triphosphate in migraine

Classical migraine is associated with two distinct phases; an initial vasoconstriction followed by vasodilatation. The “purinergic” hypothesis for migraine was originally put forward in 1981 as a basis for the reactive hyperaemia and pain during the headache phase. It was suggested that adenosine 5'-triphosphate (ATP) and its breakdown products adenosine 5'-monophosphate and adenosine were strong contenders for mediating the vasodilatation following the initial vasospasm and subsequent hypoxia. ATP was also implicated in the pathogenesis of pain during migraine via stimulation of primary afferent nerve terminals located in the cerebral vasculature. Recent studies have shown that the ATP-induced cerebral vasodilatation is endothelium-dependent via activation of P 2Y-purinoceptors on the endothelial cell surface and subsequent release of endothelium-derived relaxing factor (EDRF); and that the endothelial cells are the main local source of the ATP involved, although adenosine 5'-diphosphate and ATP released from aggregating platelets may also contribute to this vasodilatation. These findings have extended the “purinergic” hypothesis for migraine in two ways. Firstly, they have clarified the mechanism of purinergic vasodilatation during the headache phase of migraine. Secondly, they suggest that a purinergic mechanism may also be involved in the initial local vasospasm, via P 2x-purinoceptors on smooth muscle cells occupied by ATP released either as a cotransmitter with noradrenaline from perivascular sympathetic nerves or from damaged endothelial cells. migraine/purines/endothelium

NEUROTRANSMITTERS AND THE FIFTH CRANIAL NERVE: IS THERE A RELATION TO THE HEADACHE PHASE OF MIGRAINE?

The headache phase of migraine may develop as the result of an abnormal interaction (and perhaps an abnormal release) of vasoactive neurotransmitters from terminals of the trigeminal nerve with large intracranial and extracranial blood-vessels. These blood-vessels, which dilate during the headache phase of migraine, are thought to receive axonal projections from all three divisions of the trigeminal nerve. Substance P, a potent vasodilating peptide, seems to be released from trigeminal nerve endings in response to nervous stimulation and is involved in the transmission of painful stimuli within the periphery. The vasoactive molecule serotonin, implicated in the pathogenesis of migraine, coexists with substance P in some terminals of the central nervous system and is present within the trigeminal ganglia. Within this nerve serotonin may modulate the function of primary sensory neurons. The abnormal release of substance P or as yet unidentified peptides or other transmitters from the fifth cranial nerve may explain both the hemicranial pain and the vasodilation which are characteristic of the headache of migraine.

Abnormal Cerebrovascular Reactivity in Patients with Migraine and Cluster Headache

SYNOPSISCerebral vasomotor responsiveness to 5% CO 2 or 100% 0 2 inhalation or hyperventilation was tested in groups of patients with either migraine or cluster headache. Regional cerebral blood flow was measured by the 133 Xe inhalation method before and during hypercapnia, hypocapnia or hyperoxia. A series of 79 headache patients were tested (18 classic, I complicated, 37 common, 16 cluster and 7 muscle contraction). For purposes of comparison, cerebral vasomotor responsiveness was likewise tested in 48 age and sex matched healthy volunteers. CO 2 responsiveness was expressed as D%Fg (gray matter blood flow) per mmHg PECO 2 (end‐tidal CO 2 tension). Normal response was 3.6 ± 0.8% during 5% CO 2 inhalation and 3.0 ± 0.9% during hyperventilation. Inhalation of 100% O 2 inhalation reduced mean hemispheric Fg by 9.4 ± 5.4%. During the prodrome of migraine (N = 1) there was bilateral impairment of hemispheric CO 2 responsiveness. During the headache phase of migraine (N = 5) CO 2 responsiveness was impaired throughout both hemispheres but recovery occurred 24 hours after headache had subsided. During the headache‐free interval of migraine (N = 21) there was excessive cerebrovascular CO 2 responsiveness (5.1 ± 2.2%). The cerebral hemisphere on the side of predominant head pain showed significantly greater excessive CO 2 response than the “non‐headache” hemisphere. During cluster headache (N = 2) hemispheric CO 2 responsiveness was similarly impaired, but returned to normal immediately after the headache subsided. Unlike migraineurs, during cluster headache the cerebral vasoconstrictive response to 100% O 2 was excessive with marked reduction of Fg (33 ± 11%), with relief of headache. Two different types of abnormality in cerebral vascular receptor sites are hypothesized, which make it possible to differentiate migraine from cluster headache.