NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release

The aim of the present study was to investigate changes in the plasma calcitonin gene-related peptide (CGRP) concentration and platelet serotonin (5-hydroxytriptamine, 5-HT) content during the immediate headache and the delayed genuine migraine attack provoked by nitroglycerin. Fifteen female migraineurs (without aura) and eight controls participated in the study. Sublingual nitroglycerin (0.5 mg) was administered. Blood was collected from the antecubital vein four times: 60 min before and after the nitroglycerin application, and 60 and 120 min after the beginning of the migraine attack (mean 344 and 404 min; 12 subjects). In those subjects who had no migraine attack (11 subjects) a similar time schedule was used. Plasma CGRP concentration increased significantly (P<0.01) during the migraine attack and returned to baseline after the cessation of the migraine. In addition, both change and peak, showed significant positive correlations with migraine headache intensity (P<0.001). However, plasma CGRP concentrations failed to change during immediate headache and in the subjects with no migraine attack. Basal CGRP concentration was significantly higher and platelet 5-HT content tended to be lower in subjects who experienced a migraine attack. Platelet serotonin content decreased significantly (P<0.01) after nitroglycerin in subjects with no migraine attack but no consistent change was observed in patients with migraine attack. In conclusion, the fact that plasma CGRP concentration correlates with the timing and severity of a migraine headache suggests a direct relationship between CGRP and migraine. In contrast, serotonin release from platelets does not provoke migraine, it may even counteract the headache and the concomitant CGRP release in this model.     

Platelet serotonin in patients with analgesic-induced headache

The purpose of this study was to investigate the role of serotonin (5HT) in patients with analgesic-induced headache (AIH). We estimated platelet 5HT concentration in patients with AIH, migraine patients and non- headache controls, by using high performance liquid chromatography with electrochemical detection. Our results revealed a significant decrease ( p < 0.00 ) in platelet 5HT content in patients with AIH as compared to migraine patients and non-headache controls (221.8 ± 30.7, 445.3 ± 37.4 and 467.2 ± 38.5 ng/10⁹ platelets, respectively). In contrast, a difference of lesser statistical significance ( p =0.022) was observed in platelet 5HT content after incubation with excess 5HT (1940.0 ± 195.1, 2610.0 ± 173.1 and 2560 + 165.2 ng/10⁹ platelets for patients with AIH, migraine patients and non-headache controls, respectively). These data suggest that analgesic-induced suppression of 5HT uptake may interfere with the function of the pain modulatory system in the brainstem. Although the process by which analgesics interfere with this system is as vet unknown, it is possible that it may not be entirely due to defective 5HT uptake mechanisms.     

Platelet serotonin measures in migraine

OBJECTIVE AND BACKGROUND: Serotonergic mechanisms play an important role in the pathogenesis of headache. To search for potential indicators of altered serotonin homeostasis in migraine, we have investigated three parameters of the platelet serotonin (5HT) system, platelet serotonin level (PSL), platelet serotonin uptake (PSU), and monoamine oxidase (MAO-B) activity, in a group of 55 patients with migraine and in 81 healthy controls. METHODS: After platelet separation, PSL was determined fluorimetrically; PSU was measured by incubating aliquots of platelet-rich plasma with six concentrations of 14C-5-HT for 60 seconds at 37 degrees C, followed by vacuum filtration; platelet MAO-B activity (toward kynuramine as a substrate) was determined fluorimetrically. RESULTS: Values of the investigated measures, in patients versus controls, amounted to (mean +/- SD) 608 +/- 166 vs. 591 +/- 184 ng/10(9) platelets for PSL, 139 +/- 25 vs. 142 +/- 25 pmol 5HT/10(8) platelets/minute for Vmax of PSU, 376 +/- 62 vs. 404 +/- 72 nM for Km of PSU, and 15.8 +/- 5.1 vs. 14.3 +/- 5.7 nmol product/10(8) platelets/60 minutes for velocity of MAO-B. Mentioned parameters did not show statistical differences between patients and controls, with exception of a small difference in Km of PSU, reaching significance (P<0.01). After subgrouping of patients according to diagnosis (migraine with aura, migraine without aura, and migraine attack) and gender, no differences retained significance. CONCLUSIONS: Our results indicate the absence of a measurable disturbance in 5HT homeostasis in migraine, as shown by platelet 5HT parameters, and they question the suitability of the use of mentioned blood elements in this regard.     

SEROTONIN (5HT) IN MIGRAINE: LEVELS IN WHOLE BLOOD IN AND BETWEEN ATTACKS

SYNOPSIS
Fluorimetric estimations of total 5HT in blood of 11 migrainous patients during an untreated migraine attack were made. Total blood 5HT dropped during a migraine attack to about 68% of its former level returning to preheadache values by the time the pain ceased. Mean values for total blood serotonin (ng/ml) were 65.1 at the beginning of a migraine attack, 57.9 at the peak, 61.0 at the end, and 91.2 in the headache free period (p<0.05). No correlation between the intensity of the headache and the concentration of 5HT during a migraine attack was found (p>0.5). The influence of some drugs upon fluorescence in blood of migraineurs was tested.     

Are the periodic changes of neurophysiological parameters during the pain-free interval in migraine related to abnormal orienting activity?

OBJECTIVE AND METHODS: Migraine patients are characterized by increased amplitude and reduced habituation of contingent negative variation (CNV). Furthermore, the CNV underlies periodic changes during the pain-free interval, being maximal before attack. The periodicity of CNV is related to periodic changes in habituation, probably due to variation of orienting activity during the pain-free interval. CNV and orienting response (OR) were studied in 20 females suffering from migraine without aura and in 12 matched healthy females. The neurophysiological recordings in the group of patients were performed 1-4 days before and 4 days after a migraine attack. The amplitudes and habituation of early and late components and total CNV were calculated. The OR was assessed using the habituation of the skin conductance response (SCR) and alpha blocking (AB). The non-parametric tests were employed for statistical analysis. RESULTS: There were no differences between the two groups for habituation of all CNV components and of SCR following an attack. However, the habituation of AB was significantly reduced in migraine. Before attack we observed a significantly reduced habituation of the early and total CNV and of the AB compared to controls and recordings performed after an attack. The habituation of the late component and of SCR remained unchanged. CONCLUSIONS: The abnormal habituation could be explained by the periodic changes of physiological parameters during the pain-free interval. The impaired habituation of early CNV in migraine is associated with increased orienting activity seen only in the central component (AB) of OR.     

Platelet Activity in Migraine

SYNOPSIS
Migraine is a disease associated with increased platelet activity.
The aim of this paper was to study "in vivo" platelet activation by assessing platelet serotonin (5HT) content and beta-thromboglobulin (B-TG) and platelet factor four (PF4) plasma levels, in headache-free-periods and during migraine attacks.
In headache-free-periods, there was no differences in platelet 5HT values between migraine patients and control subjects. On the other hand, there were significant differences in B-TG and PF4 plasma levels. Furthermore, two groups of migraine patients were observed, one with normal B-TG plasma levels and the other with high B-TG plasma levels. PF4 plasma levels behave similarly.
During migraine attacks, platelet 5-HT fell, while B-TG and PF4 plasma levels rose, if compared to the values recorded immediately before attacks.
We suggest that migraine patients, particularly those ones with high basal values of B-TG and PF4 plasma levels, form a high risk group to cerebrovascular ischaemic diseases. For these patients a prophylaxis with antiplatelet drugs is indicated.     

Platelet serotonin pathway in menstrual migraine

In order to understand the possible 5-hydroxytryptamine (5HT) anomalies in migraine, particularly in the period before the headache attack, we compared the levels of 5HT, its stable metabolite 5-hydroxyindoleacetic acid (5HIAA) and platelet monoaminoxidase (MAO) activity in patients with menstrual migraine with those of healthy female controls. In every subject, blood samples were drawn during both follicular and late luteal phases of the menstrual cycle. In controls, platelet 5HT levels remained stable, whereas 5HIAA levels and MAO activity were higher in the luteal than in the follicular phase, suggesting an increased catabolism of 5HT which occurs physiologically just before menses. In menstrual migraine 5HIAA levels and MAO activity showed similar changes with higher values in the luteal than in the follicular phase. The luteal phase values were significantly higher than those of controls. Also, and in contrast to controls, 5HT levels decreased in the luteal phase. These data suggest that 5HT availability is reduced in menstrual migraine, possibly due to an increased catabolism and/or to a reduced synthesis, and hence predisposes patients to migraine attacks.     

Contingent negative variation during migraine attack and interval: evidence for normalization of slow cortical potentials during the attack

The contingent negative variation (CNV) amplitudes of 16 subjects with migraine without aura were studied during pain-free intervals and during attacks and the results were compared with those of 22 healthy subjects. In 32 trials the CNV amplitudes were calculated for (a) "total interval", (b) "early CNV component", (c) "late CNV component", and (d) habituation. There was a significantly higher total CNV amplitude in migraine subjects during pain-free intervals compared to that of the healthy subjects and migraine patients during an attack. Healthy subjects as well as subjects studied during the attack showed a significant habituation whereas migraine subjects studied during pain-free intervals did not. This suggests that the higher CNV amplitude in migraine patients studied between pain-free attacks may be due in part to impaired habituation.     

Abnormal habituation of 'nociceptive' blink reflex in migraine--evidence for increased excitability of trigeminal nociception

We studied the habituation of the 'nociceptive' blink reflex (nBR) in 15 healthy subjects and 17 migraine patients interictally as well as during unilateral migraine headache within six hours of onset and after treatment. In healthy volunteers the mean regression coefficient (MRC) was - 3.9 following right sided and - 4.9 left sided stimulation. This equals an amplitude loss of 19.5% (5 x -3.9) and 24.5% (5 x -4.9), respectively, across five consecutive sweeps. An augmentation of nBR responses was found in migraine patients interictally: MRC = 3.3 following stimulation of the headache side (HA) and MRC = 4.0 of the non-headache side (non-HA). The differences were statistically significant (anova: d.f. = 1, F = 25.8, P < 0.001). During the migraine attack MRCs were negative both before (-5.0, HA and - 4.0, non-HA) and after treatment (-2.6, HA and - 1.9 non-HA) and significantly differed from those outside the migraine attack (anova: d.f. = 2, F = 12.4, P < 0.001). The demonstrated lack of habituation of the nBR responses indicates an abnormal trigeminal nociceptive processing in migraine patients outside the migraine attack.     

Cognitive processing in headache associated with sexual activity

Cognitive processing in headache associated with sexual Cognitive processing as measured by event-related potentials (ERP) in patients suffering from the explosive subtype of headache associated with sexual activity (HSA type 2) was investigated. Visual ERP were measured in 24 patients with HSA type 2 outside the headache period. The differences of the first and the second part of measurement were evaluated separately to determine the amount of cognitive habituation. Twenty-four sex- and age-matched healthy subjects and 24 patients with migraine without aura served as controls. A missing increase of P3 latency during the second part of the measurement was found in 79% of patients with HSA type 2 and in 75% with migraine, but only in 17% of the healthy controls (P < 0.001). The P3 amplitude was increased during the second part in 71% of patients with HSA type 2 and in 79% with migraine, but only in 33% of the healthy controls (P = 0.02). Mean P3 latency was decreased and mean P3 amplitude was increased during the second part of the measurement in HSA type 2 and in migraine but not in the healthy control group. Patients with HSA type 2 have a loss of cognitive habituation as measured by ERP. This specific information processing is very similar to that in migraine observed in previous studies.     

The serotonergic system in migraine

Serotonin (5–HT) and serotonin receptors play an important role in migraine pathophysiology. Changes in platelet 5–HT content are not casually related, but they may reflect similar changes at a neuronal level. Seven different classes of serotoninergic receptors are known, nevertheless only 5–HT2B–2C and 5HT1B–1D are related to migraine syndrome. Pharmacological evidences suggest that migraine is due to an hypersensitivity of 5–HT2B–2C receptors. m–Chlorophenylpiperazine (mCPP), a 5–HT2B–2C agonist, may induce migraine attacks. Moreover different pharmacological preventive therapies (pizotifen, cyproheptadine and methysergide) are antagonist of the same receptor class. On the other side the activation of 5–HT1B–1D receptors (triptans and ergotamines) induce a vasocostriction, a block of neurogenic inflammation and pain transmission.     

Nitric oxide pathway, Ca2+, and serotonin content in platelets from patients suffering from chronic daily headache

An alteration in serotonin concentration has been found in patients with chronic headache caused by abuse of analgesic substances as well as an up-regulation of 5HT2 platelet receptors, which has been correlated with chronicization of the headache. In a previous study we demonstrated an increase in L-arginine/nitric oxide (NO) pathway activity in platelets from patients affected by migraine with or without aura, particularly during attacks. In the present research we assessed the variations in platelet L-arginine/NO pathway and cyclic guanosine monophosphate (cGMP) levels in 32 patients affected by chronic daily headache (CDH) (8 M, 24 F, age range 34-50 years) both during and between attacks. In these same patients, the platelet aggregation to different collagen concentrations (0.3, 1, 3 micrograms/ml) was determined as well as the intracellular platelet calcium concentration using fluorescence polarization spectrometry. These parameters were compared with those of an age- and sex-matched control group (n = 25; n = 10, n = 15, age range 35-51 years). A reduction found in platelet aggregation response to each collagen concentration used (p < 0.001) was coupled with an increased NO and cGMP production (NO: p < 0.0001; cGMP: p < 0.001). This was accompanied by a significant increase in intracytosolic Ca2+ (p < 0.0001) concentration and a reduced platelet serotonin content compared to those in control individuals (p < 0.0002). Changes in the above platelet parameters were accentuated more in patients with analgesic abuse than in CDH patients with no drug abuse. These findings suggest the occurrence of an activation of cGMP-Ca2+ mediated events in CDH patients with analgesic abuse. This physiologic compensatory mechanism, which intervenes in overcoming the increase in cytosolic Ca2+ levels, is not as efficient at limiting serotonin depletion by platelet dense bodies. A similar depletion in the central serotoninergic pathway can be assumed in the same patients.     

偏头痛患者血小板活化状态的观察

本文测定了３８例偏头痛病人和相应对照组的血小板内游离Ｃａ～（２＋）浓度和血小板聚集率的变化。结果显示：偏头痛患者血小板内游离Ｃａ～（２＋）浓度明显高于对照组，并且偏头痛发作期组明显高于偏头间歇期组（Ｐ＜０．０５），与对照组比较，偏头痛间歇期组血小板聚集率无明显变化（Ｐ＞０．０５），偏头痛发作期组血小板聚集率明显增加（Ｐ＜０．０５）。提示血小板外Ｃａ～（２＋）内流和血小板聚集率增强参与了偏头痛的症状发作．有效地抑制血小板Ｃａ～（２＋）内流对预防和治疗偏头痛将起到重要作用。     

Habituation of visual and intensity dependence of auditory evoked cortical potentials tends to normalize just before and during the migraine attack

Between attacks, migraine with (MO) or without aura (MA) patients show deficient habituation of pattern-reversal visual evoked potentials (PR-VEP) and a strong intensity dependence of auditory evoked cortical potentials (IDAP). Clinical observations of migraine prodromes and previously published electrophysiological studies suggest that cortical information processing may vary in close temporal relationship to the attack. We studied PR-VEP and IDAP just before (11 MO pts), during (23 MO, 3 MA), 1 day following (27 MO, 1 MA) and 2 days following (14 MO) a migraine attack. The results were compared with a large group of MO patients recorded at a distance of at least 3 days from an attack (n = 66 for IDAP; n = 39 for VEP). Patients recorded the day before the attack had on average an habituation of -13.6+/-20.5% (mean +/- SD) between the 5th and 1st block of 100 averaged VEP responses and a flat (0.38+/-1.06 microV/10 dB) amplitude-stimulus intensity function (ASF) slope of the auditory evoked cortical potential. Both values were significantly different from those obtained in the attack interval (P=0.003; P=0.020). During the attack, VEP habituation was less pronounced (-0.17+/-26.2%) and ASF slopes remained flat (0.32+/-1.44 microV/10 dB; P=0.002 compared to interval). During the 2 days following the attack, VEP habituation was replaced by potentiation (+0.09+/-29.1% the 1st day; 19.5+/-45.7% the 2nd day) and ASF slopes increased markedly (0.87+/-1.39 and 1.14+/-1.12 microV/10 dB). The normalization of evoked cortical responses just before and during the attack, might reflect an increase in the cortical preactivation level due to enhanced activity in raphe-cortical serotonergic pathways.     

Pathophysiologische mechanismen des Migränekopfschmerzes unter klinischen Gesichtspunkten

Migraine is more than the pain involved in the "migraine attack." Before the onset of pain many clinical symptoms can be observed. These symptoms may be classified as vegetative, affective, and vascular. Brain perfusion is altered during migraine attacks as well as during the intervals between attacks. These "more recent" findings are important because brain perfusion is controlled by metabolic and by neurotransmission mediated pathways: 750 ml blood/min is available in brain perfusion. The skull, on the other hand, limits the volume of blood in the brain to 130 ml. Control of the shift of blood inside the brain, with a chance of maximal blood flow or strictly limited blood volume, may be one of the most important problems in neurotransmission mediated cerebral perfusion control. The most important neurotransmission systems of cerebral perfusion control are those that are believed to be involved in affective and vegetative symptoms. It must be assumed that platelets are involved in migraine. Platelet reactivity is enhanced in migraine patients during the interval between attacks. When a migraine attack occurs a release of platelet serotonin and a further increase of platelet reactivity can be observed. Platelet activation in these cases is comparable to the situation in transient ischemic attacks. During transient ischemic attacks, platelet serotonin has been found to be enhanced in the area of transient ischemia. Serotonin is a neurotransmitter, low concentrations of which induce vasodilation, while higher concentrations induce vasoconstriction. It may be assumed that platelet serotonin is a potent vasoregulating substance that may interact in the brain vessels with the neurotransmission controlled perfusion. The hypothesis of an (inborn) instability of the interaction of cerebral neurotransmission systems in patients suffering from migraine is in accordance with the vegetative and affective symptoms in migraine, the observed imbalance of neurotransmission mediated cerebrovascular autoregulation and the irritation of platelets in migraine attacks, as well as in the interval between attacks. The "modern" treatments of migraine with acetylsalicylic acid, ergotamin and/or beta blockers are discussed in relation to this proposed hypothesis of a migraine pathophysiology.     

Urinary 5-HIAA in migraine: Evidence of lowered excretion in young adult females

Urinary 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in 44 young adult migraine patients (35 women, 9 men) between attacks and in 33 healthy controls (23 women, 10 men). HVA excretion was equivalent in all groups. 5-HIAA was unaltered in men but was significantly decreased in female migraine patients when compared with their sex-matched controls (-31%, p less than 0.01). No relationship was found between 5-HIAA excretion and the various characteristics of migraine, such as the time that had elapsed since the last attack and the presence or absence of oral contraception. The relatively marked decrease in 5-HIAA excretion in female migraine patients can hardly be accounted for by a reduction in either neuronal or platelet serotonin metabolism alone. A reduction in the intestinal contribution to urinary 5-HIAA might be the crucial factor.     

Cognitive processing in cluster headache

Little is known about specific changes of cognitive processing in cluster headache. Studies on event-related potentials (ERP) suggest that stimulus evaluation is impaired in chronic cluster headache and in episodic cluster headache during the cluster period, but not in the interval between two periods. Patients with chronic paroxysmal hemicrania do not show this impairment. Unlike patients with migraine, patients with cluster headache do not present with a loss of cognitive habituation as measured by ERP. In neuropsychologic evaluations, a reversible decline of memory processing was detected during the cluster attack, but not between two attacks. Long-term observation revealed no progressive cognitive decline in cluster headache patients over the years. With regard to personality changes, a liability susceptibility to anxiety disorders and to hypochondriasis, but not to mood changes, has been described inconsistently. All changes in alterations of cognitive processing in cluster headache are demonstrated to be mild and do not relevantly contribute to the clinical picture of this disease.     

Interictal lack of habituation of mismatch negativity in migraine

The aim was to study mismatch negativity features and habituation during the interictal phase of migraine. In migraine patients, a strong negative correlation has been found between the initial amplitude of long latency auditory-evoked potentials and their amplitude increase during subsequent averaging. We studied 12 outpatients with a diagnosis of migraine without aura recorded in a headache-free interval and 10 gender- and age-matched healthy volunteers not suffering from any recurrent headache. The experiment consisted of two sequential blocks of 2000 stimulations, during which 1800 (90%) recordings for standard tones and 200 (10%) for target tones were selected for averaging. The latency of the N1 component was significantly increased in migraine patients in respect of controls in both the first and second repetitions; the MMN latency was increased in the second repetition. In the control group the MMN amplitude decreased on average by 3.2 +/- 1.4 microV in the second trial, whereas in migraine patients it showed a slight increase of 0.21 +/- 0.11 microV in the second repetition. The MMN latency relieved in the second trial was significantly correlated with the duration of illness in the migraine patients (Spearman correlation coefficient: 0.69; P < 0.05). The increases in N1 latency and MMN latency and amplitude, the latter correlated with duration of illness, seemed to be due to a reduced anticipatory effect of stimulus repetition in migraine patients. This suggests that such hypo-activity of automatic cortical processes, subtending the discrimination of acoustic stimuli, may be a basic abnormality in migraine, developing in the course of the disease.     

Plasma serotonin increase during episodes of tension-type headache

The mechanisms of tension-type headache remain to be determined. Biochemical abnormalities have been rarely demonstrated. We performed a controlled study of 5-hydroxytryptamine (SHT) in platelet poor plasma obtained from 13 female patients during and between episodes of tension-type headache. The 5HT concentration in patients free of headache was not different from controls, whereas a significant increase in 5HT concentration was seen during headache ( p < 0.02.). This finding is attributed to release of 5HT from platelets or disordered 5HT metabolism during headache attacks, possibly related to pain in the latter case. We conclude that 5HT may be involved in the pathogenesis of tension-type headache but by different mechanisms than migraine.     

Serotonin metabolism in chronic tension-type headache

Serotonergic neurons play a major role in the regulation of pain and may therefore also be involved in the pathophysiology of tension-type headache. Platelets are important in the regulation of the free serotonin level in plasma and may be a model of serotonergic neurons. The aim of the present study was to investigate the peripheral serotonin (5HT) metabolism in patients with chronic tension-type headache. The 5HT levels in platelets and in plasma, the beta-thromboglobulin (ß-TG) levels in plasma, and the urinary excretion of 5-hydroxyindoleacetic acid (5HIAA) were measured in 40 patients with chronic tension-type headache and in 40 healthy controls. The platelet uptake index was calculated as the ratio between platelet 5HT and plasma 5HT levels. There were, no significant differences in platelet 5HT, plasma 5HT ß-TG, or 5HIAA between patients and controls. The platelet uptake index was significantly lower in patients 243 (136–367) than in controls 352 (202–508), p =0.03. Our results indicate that the peripheral 5HT metabolism is largely normal in patients with chronic tension-type headache.