PLASMA FREE FATTY ACIDS AND PROSTAGLANDIN E1 IN MIGRAINE AND STRESS

SYNOPSIS
The relationship of plasma FFA, plasma PGE₁ and platelet serotonin changes were investigated in migrainous patients and in patients subjected to stressful procedures.
Plasma FFA levels rose and platelet serotonin content fell during the migrainous episode in the majority of patients. These changes were statistically significant. Plasma FFA levels and platelet serotonin changed reciprocally in 60% of cases. No statistically significant change in plasma FFA levels were observed in patients subjected to stressful procedures or during cluster headache.
Plasma levels of PGE₁ showed no significant change during migraine. No difference in PGE₁ between venous and arterial plasma was found in normal subjects and in patients with various neurologic diseases. Plasma levels of natural PGE₁ do not accurately reflect the rate of PGE₁ synthesis in the body and this may account for these negative results.
The migraine attack is accompanied by a rise in plasma FFA. However, this rise is not necessarily the cause for serotonin release which occurs during migraine. Both the amine and PGE₁ could release FFA from body stores. Identification of the individual FFA released would be necessary to resolve the problem. The role of PGE₁ in migraine, might be assessed by estimation of its more stable 15-keto-dihydro metabolite which reflects more accurately its rate of synthesis. This could demonstrate whether PGE 1 plays a part in the biochemical process of headache.     

Increased cerebrovascular pCO2 reactivity in migraine with aura- a transcranial Doppler study during hyperventilation

Cerebrovascular reactivity during hypocapnia was tested in 20 migraineurs (8 with aura, 12 without aura) and 30 sex- and age-matched healthy subjects, and during nitroglycerin-induced headache in 12 healthy subjects. Before and during hyperventilation, mean blood-flow velocity (V_mean) in the middle cerebral artery was measured with transcranial Doppler. In each subject a pCO₂ reactivity index (RI) was calculated as DV_mean/baseline V_mean)/ DpCO₂. Interictally, patients with migraine with aura showed higher RI ( p < 0.05 ANOVA and multiple range test) than controls, whereas migraineurs without aura did not differ from healthy subjects. Ictal and interictal RIs were similar in 9 patients suffering from migraine without aura. No side-to-side differences were detected in RI. During nitroglycerin-induced headache, the RIs were no different from those recorded during migraine attacks and in non-nitroglycerin-provoked healthy controls (p > 0.05, ANOVA and multiple range test). The exaggerated response in migraine with aura might predispose for the characteristic changes in rCBF seen during attacks.     

Prostaglandin - E 2 Levels in the Saliva of Common Migrainous Women

SYNOPSIS
Prostaglandin E₂ (PG-E₂) levels were measured in the saliva of 6 women suffering from common migraine, during an attack, and in the interval between attacks; the results obtained were compared to the levels found in a matched control group of healthy women. There was a significant increase in the levels of PG-E₂ during migraine attack P<0.05. These results may suggest that PG-E₂ takes an important role in the mechanism of migraine.     

Pharmacokinetics of rizatriptan tablets during and between migraine attacks

Gastric stasis during migraine attacks results in delayed absorption of several orally administered antimigraine agents. This study, as part of a larger trial, was conducted to examine the pharmacokinetics of rizatriptan tablets during and between migraine attacks. Participating patients met IHS criteria for migraine with or without aura, and suffered between one and eight migraines per month for the previous 6 months. In part 1 of the study, 21 patients were randomized to receive a single 5-mg tablet of rizatriptan or placebo in the migraine-free state. In part 2, the same patients were treated during migraine with rizatriptan 5-mg tablets (n=18) or placebo (n=3). Blood samples were obtained before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after dosing. The plasma concentration profile (ie, AUC_(0-∞), C_max, T_max) of rizatriptan 5-mg tablets administered during and between migraine attacks were comparable. The median T_max for rizatriptan between and during attacks was 1 hour, indicating rapid absorption even during a migraine attack. Rizatriptan 5 mg was well tolerated and 67% of the patients experienced headache relief 2 hours postdose.     

Identification of Blood Leukotrienes in Classical Migraine

SYNOPSIS
In five patients affected by classical migraine a longitudinal study was performed, dealing with the in vitro parameters of platelet aggregation, during prodromal, attack, post-attack and interval phases. These patterns were compared with the analysis of blood leukotrienes, carried out by use of analytical reversed phase HPLC. Presence of leukotriene C₄ (LTC₄) during prodromal and attack phases, corresponded to a transient inhibition of epinephrine-induced aggregation. Recovery towards normal or increased values of platelet aggregation occurred during both post-attack and interval phases, which were accompanied by the presence in blood of 5–12 di-hydroxyeicosatetraenoic acid (5–12 DHETE) and/or leukotriene B₄ (LTB₄) respectively, and by their subsequent metabolic breakdown products. Hypotheses on the role of leukotrienes in the pathogenesis of migraine are discussed.     

Concentration and uptake of 5-hydroxytryptamine in platelets from cluster headache and migraine patients

Concentrations of 5-hydroxytryptamine (5-HT) in platelets were determined in 33 cluster headache patients (17 males) and in 34 migraine patients (16 males) outside attacks. The 5-HT uptake into platelets was measured and the kinetic constants V_max and K_m determined in 26 cluster patients (14 males) and in 30 migraine patients (13 males). Significantly lower 5-HT concentrations in whole blood were found in cluster headache and migraine patients than in 50 healthy controls (19 males). The V_max and K_m values of the 5-HT uptake were significantly lower in cluster headache and migraine patients compared with 22 healthy controls (9 males). The 5-HT concentrations and the kinetics of the 5-HT uptake did not differ between cluster headache and migraine. In healthy controls a significant positive correlation was found between the 5-HT uptake rate at 0.25 μM and K_m but not in cluster headache and migraine patients. The 5-HT concentrations in whole blood correlated positively with V_max and K_m, respectively, in cluster headache and with K_m in healthy controls but not with V_max nor with K_m in migraine. There was no obvious relation between the kinetics of platelet monoamine oxidase (MAO) and the 5-HT uptake except for an increased incidence of low V_max of MAO and low K_m of the 5-HT uptake in cluster headache. The kinetics of the 5-HT uptake was apparently not related to the state of migraine. The results indicate a possible constitutional trait in cluster headache and migraine expressed as low 5-HT concentrations in whole blood and low V_max and K_m of the 5-HT uptake into platelets.     

Decreased Thromboxane Production in Migraine Patients During Headache-Free Period

SYNOPSIS
To study the role of the proaggregatory, vasoconstrictory thromboxane A ₂ (TxA ₂ ) in migraine, the plasma levels of Thromboxane B ₂ (TxB ₂ ), the stabile metabolite of TxA ₂ , were measured from 14 adults and 8 children with migraine during the attack-free interval. In addition, the platelets' capacity to generate TxB ₂ during spontaneous clotting was studied. The plasma TxB ₂ concentrations were lowered in the adult migraine patients. Also the platelets' capacity to produce TxB ₂ was reduced in migraine children and in adults with classic migraine. The decreased platelet TxA ₂ synthesis in the attack-free period of migraine patients may reflect a deficient pool of platelet arachidonic acid, the precursor of TxA ₂ , perhaps as a result of increased consumption during migraine attacks.     

Increased 11-dehydrothromboxane B 2 in Migraine: Platelet Hyperfunction in Patients with Migraine during Headache-free Period

SYNOPSIS
Several disturbances in platelet function have been reported in migraine and tension-type headache (TH). The plasma 11-dehydrothromboxane B ₂ (11-dTXB ₂ ) is free from artifactual increase during blood sampling, and it can be a reliable indicator of thromboxane A ₂ (TXA ₂ ) production in vivo. TXA ₂ is a very potent proaggregatory and vasoconstrictory metabolite formed in the platelets. We investigated plasma 11-dTXB ₂ and 5-hydroxytryptamine (5-HT) levels in patients with migraine during headache-free periods and in patients with chronic TH. The mean value of plasma 11 -dTXB ₂ levels in migrainous patients was significantly higher than those in TH patients and healthy controls. The mean value of plasma 5-HT levels in TH patients was significantly lower than those in migrainous patients and healthy controls. There was no correlation between plasma 11-dTXB ₂ levels and plasma 5-HT levels in any group. The results suggest the existence of continuous platelet activation in migrainous patients.     

Platelet Activation and Migraine: A Study with Flunarizine

SYNOPSIS
Although in common and classic migraine there is platelet activation both during painful attack and headache-free periods, the role of platelets in migraine pathogenesis is not yet understood. Therefore, in order to investigate the relationship between platelets and migraine pathogenesis, β-thromboglobulin (β-TG) and platelet factor four (PF₄), both platelet-specific alpha granule proteins, were assayed in a group of patients with classic and complicated migraine before and after administration of an anti-migraine drug, flunarizine, at a dose of 10 mg/daily. Blood samples for β-TG and PF₄ assay were collected for ten days in which the patients were headache-free. β-TG and PF₄ plasma levels were elevated in all patients in comparison with control subjects. The patients with complicated migraine showed the highest plasma values. During flunarizine treatment β-TG and PF₄ levels persisted elevated in all patients, although a slight decrease of β-TG plasma levels was observed. This data confirmed, as our previous works, that classic migraine is characterized by platelet activation "in vivo," but that this may not be strictly related to migraine pathogenesis.     

5HT2 receptors in cerebral cortex of migraineurs studied using PET and 18F-fluorosetoperone

Since the brain 5HT₂ receptors might be implicated in migraine pathogenesis, we have used positron emission tomography and ¹⁸F-fluorosetoperone, a 5HT₂ specific radioligand, to investigate in vivo the cortical 5HT₂ receptors in migraine subjects. Nine migraineurs who had either migraine with and without aura ( n = 5) or only migraine without aura ( n = 4) were studied between attacks. Twelve unmedicated healthy subjects of similar mean age were used as controls. Brain radioactivity was measured after ¹⁸F-setoperone IV injection for 90 min. A decrease of the regional specific distribution volumes (SDV) of the ligand was observed both in migraineurs and in controls. The age adjusted group means of SDV did not differ between patients and controls for the whole and for the right or left frontal, temporal, parietal and occipital cortex. These results suggest that cortical 5HT₂ receptors may be unaltered between attacks in migraine sufferers.     

Platelet activity in cluster headache

Platelets are known to be activated in common or classic migraine both during the attack and in headache-free periods. Platelet behavior is less well known in cluster headache. We have investigated beta-thromboglobulin (beta-TG) and platelet factor four (PF4) plasma levels, markers of in vivo platelet activation, in patients during remission and during bouts of cluster headache with and without pain. The results indicated that statistically significantly higher levels of beta-TG and PF4 occur in the patients during the remission period when compared with the control subjects. Such high levels seemed to persist between paroxysmal episodes in cluster periods. However, during the attacks of cluster headache beta-TG and PF4 plasma levels decreased by 42% and 50%, respectively, in comparison with plasma concentrations measured outside of attack. Thus, although platelet activation also occurs in patients with cluster headache, the attack as such seems to be characterized by a marked reduction in platelet activation.     

Altered release of endothelin-1,2 and thromboxane B2 from trophoblastic cells in pre-eclampsia

The aim of the study was to investigate whether pre-eclampsia is associated with an altered release of vasoactive substances from trophoblastic cells in vitro . Trophoblastic cells from 15 uncomplicated control pregnancies and 18 pre-eclamptic pregnancies at preterm (weeks 31–36; n  = 12) and term (weeks 37–40; n  = 21) were cultured for 5 days. The concentrations of angiotensin II (AII), endothelin-1,2 (ET-1,2), thromboxane B₂ (TXB₂), 6-keto-prostaglandin F_1α (6-keto-PGF1_α) and leukotriene B₄ (LTB₄) were measured daily in culture media for 5 days by radioimmunoassay. In pre-eclampsia, concentrations of ET-1,2 were decreased ( P < 0.01) at both preterm and term, TXB₂ concentrations were increased P < 0.05) only at preterm and the TXB₂–6-keto-PGF_1α ratio was increased at both preterm and term ( P < 0.01) as compared with the controls. Concentrations of AII, 6-keto-PGF_1α and LTB₄ were similar to the controls. The data suggest that pre-eclampsia is associated with a decreased release of ET-1 and an increased release of TXB₂ from trophoblastic cells in vitro     

The Event-Related Potential P300 During Headache-Free Period and Spontaneous Attack in Adult Headache Sufferers

The event-related potential P300 has been studied in 15 migraine without aura sufferers, and in 15 episodic tension-type headache sufferers, during pain-free periods and during spontaneous headache attacks. There were no variations of potential, either of P₃ latency or N₂ -P₃ amplitude, in either group during the interictal period. Similarly, there were no variations of the P300 parameters in the group of tension-type headache subjects during headache attacks; by contrast, a significant elongation of latency ( P <0.01) and an increment of N₂-P₃ wave amplitude ( P <0.002) was observed in the group of migraineurs. The authors discuss the data in accordance with the etiopathogenic theories of migraine and the hypothesis that acetylcholine and norepinephrine are the neurotransmitters able to affect the event-related potential P300, which reflects cerebral activity during sensory information processing and analysis.     

Provocation of Unilateral Pain in Cluster Headache Patients by Breathing CO2

Ten patients with cluster headache in an active period and 6 controls were studied as to heart rate, blood pressure, blood flow in the common carotid arteries (CCA), end-tidal PCO₂ and pain before, during and after 6 minutes of breathing 6% CO₂ In air. Heart rate increased significantly during C0₂ breathing in controls but not in patients. The cluster headache patients had significantly lower baseline end-tidal PCO₂ than controls. CCA blood flow increased significantly during CO₂ breathing in both groups. Vascular resistance decreased during CO₂ provocation and increased above baseline levels 5 minutes after provocation in both groups and related to the end-tidal PCO₂. Six of eight cluster headache patients, who had an increase of blood flow at provocation, reported slight to moderate unilateral pain in relation to the CO₂ provocation in contrast to controls.
One patient treated with 6 mg sumatriptan 2.5 hours before the provocation had an end-tidal PCO₂ within the range of the controls, and did not get an increase of CCA blood flow or pain at provocation.
Six of the cluster headache patients were restudied when out of the active period. There was still no heart rate increase during CO₂ breathing and end-tidal PCO₂ was still lower than in the controls. Unilateral headache was not provoked.     

Cluster Headache: Transcranial Doppler Assessment of Dynamic Cerebral Circulatory Changes During Hypocapnia and Attack

SYNOPSIS
Transcranial Doppler ultrasound (TCD) investigations have been carried out in cluster headache patients (8 during remission and 6 during bout) and 14 healthy subjects, to assess cerebral vasomotor reactivity (VMR) to hypocapnia induced by voluntary hyperventilation. VMR was expressed as the relative change in blood flow velocity (V) (%) as a function of the reduction in end-tidal PCO₂ (P_ETCO₂) (kPa), i.e. V/P_ETCO₂. TCD with simultaneous P_ETCO₂ monitoring, was also performed in 5 patients during spontaneous attacks.
Prior to hyperventilation, there was bilaterally lower anterior cerebral artery velocity (V_ACA) during the bout than during remission (P <0.05 on the symptomatic side), and also lower than in the controls. During remission, V_ACA was higher on the symptomatic side than on the other side (P <0.05). ACA also showed a lower VMR during the bout than during remission, and it was also lower than in controls (bout vs. remission on the non-symptomatic side, P <0.01; on the symptomatic side, P > 0.1). Approximately 30 minutes after the onset of attack, P_ETCO₂ started to decrease gradually from 4.65 to 4.10 kPa in one patient with severe attack. The V_ACA decreased markedly and bilaterally already at an early stage of the attack, i.e. prior to the hyperventilation. Middle cerebral artery velocity tended to decrease 30 minutes after the onset of attack on the symptomatic side, and 50 minutes after onset on the non-symptomatic side. It is concluded that the vascular hanges observed most likely are secondary phenomena during the cluster headache attack.     

Prolactin in cluster headache: Diurnal secretion, response to thyrotropin-releasing hormone, and relation to sex steroids and gonadotropins

The diurnal rhythmicity of serum prolactin (PRL) and the PRL and thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) were studied in 31 cluster headache patients (4 chronic cases) and 14 healthy controls. Sixteen of the patients were studied both during clinical remission and headache periods. In males the nocturnal PRL peak was blunted during remissions as compared with that in cluster periods and that in control individuals. The 24-h mean PRL levels were lower during remission and cluster periods than in the controls. There were no significant differences in the PRL levels between female patients and controls. Headache attacks were often associated with increases of serum PRL levels. The PRL reponse to TRH was lower in the female patients but not in the male patients as compared with controls. The maximum testosterone levels were lower during cluster periods than during clinical remission but not when compared with controls. Serum levels of luteinizing hormone, follicle-stimulating hormone, progesterone, estradiol, T₃, T₄, and TSH did not differ between patients and controls. The results suggest an altered regulation of PRL secretion not only during active cluster periods but also during symptom-free intervals. The possible influence of sleep, estradiol, testosterone, medication, pain, and serotoninergic and dopaminergic mechanisms are discussed.     

Blood Leukotrienes in Headache: Correlation With Platelet Activity

Platelet hyperactivity, one of the commonest findings associated with migraine, has been related to increased release of biologically active substances such as catecholamines and arachidonic acid metabolites, which seem to play a role in the pathogenesis of migraine. In this study, in vitro platelet aggregation tests were performed on samples from patients with different types of headache. The presence of platelet hyperactivity was clearly demonstrated in 11 patients with classical migraine between attacks, but not in 4 patients between attacks of common migraine. Nevertheless, the presence of a marked platelet hyporesponsivity was found during the attack phase of both classical and common migraine. No difference in platelet aggregability was found between attack and post-attack phases in 5 patients with cluster headache. Blood leukotrienes were analyzed in 8 patients with classical migraine and in the 5 patients with cluster headache. During the attack phase of classical migraine both LTC4 and LTB4 were present in the peripheral blood, while the post-attack phase was characterized by the disappearance of LTC4 and the presence of LTB4 and its transisomer delta 6-trans-LTB4. Blood leukotrienes were constantly absent during both phases of cluster headache. Incubation of normal platelets with LTC4 or delta 6-trans-LTB4 was followed by inhibition of platelet response to epinephrine. delta 6-trans-LTB4, at higher concentrations, induced the opposite effect. A possible role of blood leukotrienes in the changes occurring in platelet aggregability during the different phases of classical migraine, is discussed.     

Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine

We hypothesized that intravenous infusion of the parasympathetic transmitter, vasoactive intestinal peptide (VIP), might induce migraine attacks in migraineurs. Twelve patients with migraine without aura were allocated to receive 8 pmol kg⁻¹ min⁻¹ VIP or placebo in a randomized, double-blind crossover study. Headache was scored on a verbal rating scale (VRS), mean blood flow velocity in the middle cerebral artery ( V _{mean MCA}) was measured by transcranial Doppler ultrasonography, and diameter of the superficial temporal artery (STA) by high-frequency ultrasound. None of the subjects reported a migraine attack after VIP infusion. VIP induced a mild immediate headache (maximum 2 on VRS) compared with placebo ( P  = 0.005). Three patients reported delayed headache (3–11 h after infusion) after VIP and two after placebo ( P  = 0.89). V _{mean MCA} decreased (16.3 ± 5.9%) and diameter of STA increased significantly after VIP (45.9 ± 13.9%). VIP mediates a marked dilation of cranial arteries, but does not trigger migraine attacks in migraineurs. These data provide further evidence against a purely vascular origin of migraine.     

Chronic Cluster Headache: Provocation With Carbon Dioxide Breathing and Nitroglycerin

Nine patients with chronic cluster headache were studied as to end-tidal PCO₂ , heart rate, blood pressure, common carotid artery blood flow, vascular resistance, and intensity and duration of painbefore, during, and after breathing 6% CO₂ in air for 6 minutes and before and after administration of 1 mg nitroglycerin sublingually. End-tidal PCO₂ was low at rest without provocation indicating that chronic cluster head. ache patients hyperventilate. Carbon dioxide provocation induced an increase in common carotid artery/blood flow. This provocation, previously shown to induce pain in episodic cluster headache patients, did not result in unilateral pain in chronic cluster headache patients. Nitroglycerin did not provoke any pain in 4 of 5 chronic cluster headache patients in contrast to the effects in episodic cluster headache patients in a cluster period. In one chronic cluster headache patient, short-lasting attack of moderate pain intensity was provoked. The results agree with the hypothesis that chronic cluster headache patients have changed vascular reactivity due to permanent sympathicoplegia unilaterally in the middle fossa in contrast to episodic cluster headache patients who it has been suggested have a nonpermanent sympathicoplegia unilaterally in the same region.     

Cluster Headache: The Peripheral Chemosensitivity as Indicated by the Single-Breath CO2 Test

SYNOPSIS
A single-breath CO₂ test was carried out in cluster headache patients both during bout and remission, and in matchedhealthy individuals (n = 10 for each group) to assess peripheral chemosensitivity. The test subjects inhaled one tidal breath of13% CO₂ in air. The response was expressed as the maximal increase in inspiratory minute ventilation (V_I) within 20 secondsfrom the exposure to CO₂, divided by the increase in end-tidal PCO₂ (P_ETCO₂) (the difference in PCO₂ between the testbreath and the preceding control breaths): DV_I/DP_ETCO₂.
Under the initial resting condition, cluster headache patients within the bout showed a slight hyperventilation in that therewas a significantly reduced P_ETCO₂ (P < 0.05, Student's paired t-test), and during remission, higher V_I, and a lower P_ETCO₂ (P < 0.05, Wilcoxon signed rank test), in comparison with the controls. There was no statistically significantdifference as regards the peripheral chemosensitivity between cluster headache and control groups. These results indicatethat cluster headache patients have an intact and properly-functioning carotid body.