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.     

Up-regulation of 5-HT2 Serotonin Receptor: A Possible Mechanism of Transformed Migraine

SYNOPSIS
Transformation of episodic migraine to chronic daily headache (so called transformed migraine) ia now a well recognized phenomenon. Although several factors, i.e. analgesic overuse, increasing age, psychiatric disorders are reported to play some roles in this transformation, the precise cascade is still unclear. Further suppression of an already abnormal antinociceptive system with up-regulation of post-synaptic receptors is one of the possible explanation. In order to understand the mechanism underlying this condition, 5-HT₂ serotonin receptors on platelets were assayed by the radioligand binding technique. Six transformed migraine patients (67.67 ± 1.52 years) and seven healthy controls (72.86 ± 1.82 years) were studied. [³H]-spiperone and ketanserin were used to determine the specific binding. We found a significant increase (P <0.05) in the maximal receptor numbers (B_max ) on platelet membrane of the migraine patients when compared to the controls (64.31 ± 11.06 end 39.96 ± 5.42 fmol/mg protein, respectively), whereas the dissociation equilibrium constant (K D ) values remained unchanged (3.63 ± 0.78 nM and 2.84 ± 0.48 nM for the migraine patients and controls, respectively). The up-regulation of serotonin receptors found in this study provided further support to the "serotonergic hypofunction" theory of migraine pathogenesis and may explain the unusual loss of episodicity seen in the transformed migraine patients.     

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.     

Migraine Patients Show Increased Platelet Vasopressin Receptors

This study was designed to investigate vasopressin receptor status (B_max and K_d) on platelets, vasopressin plasma levels, and vasopressin-induced platelet aggregation in migraine patients (21 females and 6 males) during a headache-free interval and in a matched control group. In the migraine group, B max was significantly higher ( P = 0.02) at 53.9 ± 20.6 fmol/mg than in the control group (36.8 + 21.0 fmol/mg). A correlation between B_max and high or low sensitivity to vasopressin as an aggregator was evident in the control group, but not in the migraine group. No differences in K_d or in plasma levels of vasopressin between the migraine and control group were apparent. Men in both groups were much less sensitive to vasopressin as a platelet aggregator than were women ( P < 0.01). Whether the higher B_max in the migraine group is a reflection of temporarily higher vasopressin levels during headache or reflects a primary increase in sensitivity to vasopressin, remains to be clarified. The higher sensitivity of platelets (as a model for vessel wall receptors) from women may indicate why many more women than men suffer from migraine. Since the B_max of the vasopressin receptor on platelets from migraine patients is increased compared to controls, treating migraine headache with vasopressin may deserve more attention.     

Platelet Alpha2-Adrenoceptor Binding in Migraine

SYNOPSIS
Platelet alpha 2 -adrenoceptor binding was determined in ten migraine patients and sixteen healthy controls using (³H)-yohimbine as radioligand. The mean value of maximum binding (^Bmax ) in the migraine patients was 133 ±55 binding sites/ platelet which is significantly lower than that of 217 ± 76 binding sites/platelet in controls (p<0.01). There was also a significant difference in the mean dissociation constant (K_D ); 2.05 ± 0.44 nM in migraineurs and 2.98 ± 1.15 nM in controls (p<0.05). Platelet alpha 2 -adrenoceptors may constitute valid models for certain characteristics of alpha 2 -adrenoceptors in the brain. An alteration in platelet alpha₂ -adrenoceptor binding may thus reflect similar alterations in central alpha₂ -adrenoceptors. It is also discussed whether the alpha₂ -adrenoceptor abberrations are intrinsic to migraine or a result of endogenous and/or pharmacologically induced modulation.     

Derangement of Serotonin System in Migrainous Patients With Analgesic Abuse Headache: Clues From Platelets

Accumulating evidence indicates that serotonin (5-HT) may be involved in the process of analgesic-induced headache transformation. In order to clarify this hypothesis, we investigated the 5-HT system in migraine patients with analgesic abuse headache by using platelets as a neuronal model. Our results revealed a significant decrease in platelet 5-HT content in these patients compared to migraine patients and nonheadache controls (179.24 ± 10.18, 451.22 ± 14.35, and 480.22 ± 13.98 ng/10⁹ platelets, respectively; P <0.001). This biochemical result was well correlated with a significant decrease ( P 2/cells, respectively). As this canaliculi system plays a significant role in the platelet secretory response, such dilatation may imply an excessive release of substances from this system. Based on this platelet model, we suggest that excessive use of analgesics alters the central 5-HT system by depleting 5-HT from its storage sites and results in the hyposerotonergic state. This analgesic-induced 5-HT alteration may be a possible mechanism of headache transformation observed in this condition.     

The antagonist properties of S 11978 on 5HT3 receptors in N1E-115 neuroblastoma cells

Summary— The effects of the novel antagonist S 11978 (Endo-7-[(8-methyl-8-azabicyclo[3,2,1]-3-octyl)oxycarbonyl] benzo[b] thiophene) on 5HT₃ receptors were examined in N1E-115 mouse neuroblastoma x rat glioma hybrid cells, with radioligand binding and whole cell patch clamp techniques. The 5HT₃ receptor ligand [³H] quipazine was displaced by ICS 205–930, GR 38032F and S 11978 with K_I values of 2.25 nM, 36.5 nM and 1.75 nM respectively. Electrophysiological studies showed that S 11978 is a potent 5HT₃ antagonist: IC₅₀ values for inhibition of 5HT-induced inward current by ICS 205–930, GR 38032F and S 11978 were 0.22 nM, 0.63 nM and 0.43 nM respectively at a holding potential of-65 mV. It is concluded that S 11978 is a potent, high affinity 5HT₃ receptor antagonist.     

Naratriptan: biological profile in animal models relevant to migraine

The biological profile of naratriptan (N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulphona-mide), a novel 5HT_1B/1D receptor agonist, was investigated in a variety of experimental models of relevance to migraine. Naratriptan has high affinity for human recombinant 5HT_1B and 5HT_1D receptors (pKi = 8.70.03 and 8.30.1, respectively) and causes contractions of dog isolated basilar and middle cerebral artery (EC₅₀ values of 0.11 and 0.07 M, respectively). Naratriptan causes small contractions of human isolated coronary arteries (EC₅₀ value of 0.17 M; maximum contraction equivalent to 33% of 5HT maximum). In anaesthetized dogs, naratriptan causes selective vasoconstriction of the carotid arterial bed (CD₅₀ dose = 193 g kg⁻¹) and, in anaesthetized rats, naratriptan selectively inhibits neurogenic plasma protein extravasation in the dura (ID₅₀ = 4.1 g kg⁻¹). In a variety of antinociceptive tests, naratriptan has no effect even at high doses. In conscious rats and dogs, naratriptan has high oral bioavailability (71% and 95%, respectively). The data show that naratriptan is a selective agonist at 5HT_1B/1D receptors, with a pharmacological profile very similar to that of sumatriptan, albeit 2-3 fold more potent. These observations, coupled with high oral bioavailability in animals, suggest that naratriptan has the profile of an orally effective anti-migraine drug.     

Autoradiographic distribution of [3H]sumatriptan-binding sites in post-mortem human brain

The anatomical distribution of [³H]sumatriptan-binding sites was analysed in brain tissue sections from 11 subjects. Relevant concentrations of [³H]sumatriptan-binding sites were seen in areas such as visual cortex>locus niger>globus pallidus>layers IV-V of the frontal cortex>subiculum>entorhinal cortex>nucleus tractus solitarius>nucleus trigeminalis caudalis. This distribution of [³H]sumatriptan-binding sites in the human brain shows some differences when compared with that of 5HT_1D receptors, confirming that, besides 5HT_1D,sumatriptan also binds to 5HT_1F receptor subtype. Some species differences are evident between the distribution of [³H]sumatriptan-binding sites in the human brain and that reported for guinea-pig and rat brains, emphasizing that caution is needed in extrapolating experimental data from animals to humans. Furthermore, these data help to explain some of the therapeutic actions of sumatriptan. The remarkable levels of binding found in areas such as nucleus tractus solitarius and nucleus trigeminalis caudalis suggest that in migraine attacks sumatriptan could exert its specific anti-emetic effects and, partly at least, induce analgesia by directly acting over these brain nuclei.     

Differential effects of the 5HT1B/1D receptor agonist naratriptan on trigeminal versus spinal nociceptive responses

In vivo electrophysiological assays in anesthetized rats have been used to compare the effects of the 5HT_1B/1D receptor agonist, naratriptan, on central trigeminal nociceptive processing from dural and cutaneous inputs with its effects on nociceptive processing in the spinal cord. Naratriptan inhibited responses of single trigeminal neurons, to noxious electrical and mechanical stimulation of the dura and face, dose dependently by a maximum of 67±3% and 70±18%, respectively, at 3 mg kg⁻¹ i.v. In contrast, naratriptan did not affect spinal dorsal horn neuronal responses to noxious mechanical stimulation of the hind-paw. These findings suggest that 5HT_1B/1D receptors have differential effects on nociceptive processing in the trigeminal versus spinal dorsal horns and provide a potential explanation for the lack of general analgesic effects of brain penetrant 5HT_1B/1D agonist antimigraine drugs.     

Plasticity of 5-HT serotonin receptor in patients with analgesic-induced transformed migraine

Chronic drug exposure can induce a significant change in neurotransmitter receptor systems and is possibly involved in the pathogenesis of drug-induced neurological disorders. Abuse of analgesics is known to induce deterioration in headache status in patients with primary headaches, especially migraine. To assess the possibility of 5-HT2A serotonin receptor plasticity in this condition, we investigated receptor binding on the platelet membrane in patients with analgesic-induced transformed migraine, patients with migraine, and nonheadache controls. Various concentrations of [3H]-spiperone (0.4 to 12 nmol) was used as a radioligand, and ketanserin was used to determine nonspecific binding. A lower maximal number of receptors (Bmax) was observed in patients with migraine as compared to patients with transformed migraine, and controls (467 +/- 58, 708 +/- 36, and 786 +/- 64 fmol/mg protein, respectively, P<0.01); whereas the value of the dissociation equilibrium constant (Kd) remained unchanged (1.72 +/- 0.16, 1.41 +/- 0.13, and 1.25 +/- 0.21 nmol for patients with migraine, patients with transformed migraine, and nonheadache controls, respectively). A significant decrease in Bmax value was observed in patients with transformed migraine after 4 weeks of analgesic withdrawal (770 +/- 25 and 345 +/- 31 fmol/mg protein, P<0.001), whilst no significant change in Kd value was observed (1.95 +/- 0.12 and 2.47 +/- 0.30 nmol, respectively). These findings indicate that 5-HT2A serotonin receptor system is altered in patients with transformed migraine with analgesic overuse. Such receptor plasticity may be an important step in the pathogenic mechanism of transformed migraine.     

Responsiveness of non-IHS migraine and tension-type headache to sumatriptan

In a long-term efficacy and satiety study, 424 patients were treated with sumatriptan (6 mg sc) for 1,904 migraine attacks. The patients were diagnosed with migraine based on IHS criteria but individual migraine attacks treated in the study were physician diagnosed; not necessarily required to meet IHS criteria. A re-analysis of the treatment response to open label sumatriptan (6 mg sc) indicated that 43 patients had treated at least one migraine that fulfilled IHS criteria for tension-type headache. Analysis of this population revealed they treated 232 headaches. Of these headaches, 114 were classified per IHS criteria as migraine; 76 as tension-type; and 42 as. non-IHS migraine (not classifiable as IHS migraine or IHS tension-type headache). Of the 114 migraines a positive response to sumatriptan occurred in 109 (96%) cases; of the 76 tension-types, 73 responded to sumatriptan (97%); of the 42 non-IHS migraine, 40 (95%) responded to sumatriptan. An equivalent response to sumatriptan among three diagnostic groups of headache supports the concept of a common biologic mechanism involving 5HT₁ receptors that spans a range of clinical presentations.     

Pathophysiology and pharmacology of migraine. Is there a place for antiemetics in future treatment strategies?

This article reviews the pathophysiology and pharmacology of emesis in relation to migraine pathogenesis. Also, the place of antiemetic and gastrointestinal prokinetic agents in current and future acute migraine treatment strategies is reviewed. The mechanisms of action of current and novel acute migraine therapies are considered with respect to the neurogenic and vascular hypotheses. Control of migraine-associated nausea and vomiting is often achieved with the benzamide dopamine D₂ receptor antagonist metoclopramide. This drug also has 5HT₃ receptor antagonist activity and reproducibly stimulates gastric motility to increase the availability of orally administered drugs. Other antiemetic and gastroprokinetic agents with potential value for the treatment of migraine-associated nausea and vomiting could speed absorption of oral antimigraine therapies without central nervous system side effects. Domperidone, a dopamine D₂ receptor antagonist that does not cross the blood brain barrier is relatively free of the central side-effect liability of metoclopramide. Cisapride, a benzamide 5HT₄ receptor agonist gastrointestinal prokinetic drug, lacks dopamine antagonist activity. A controlled comparison of these agents as migraine co-therapies could provide information on the importance of peripheral and central mechanisms in migraine-associated nausea and vomiting and improve antimigraine treatment options.     

Methysergide

Methysergide is a semisynthetic ergot alkaloid ergometrine derivative, introduced in pharmacotherapy for migraine prophylaxis as a specific serotonin (5HT) receptor antagonist. Methysergide is not just a 5HT₂ antagonist, it is also a 5HT₁ agonist. Open and controlled studies attest to methysergide's efficacy. It may be more effective in resistant cases with a high attack frequency and may act synergistically with ergotamine and dihydroergotamine (DHE) for breakthrough attacks. Contraindications include pregnancy, peripheral vascular disorders, severe arteriosclerosis, coronary artery disease, severe hypertension, thrombophlebitis or cellulitis of the legs, peptic ulcer disease, fibrotic disorders, lung diseases, collagen disease, liver or renal function impairment, valvular heart disease, debilitation, or serious infection. Methysergide can induce retroperitoneal fibrosis and pleural and heart valve fibrosis with an estimated incidence of 1 in 5,000 treated patients. Therefore, it should be reserved for severe cases in which other migraine preventive drugs are not effective.     

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.     

The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

Headache induced by serotonergic agonists—a key to the interpretation of migraine pathogenesis?

Serotonergic agonists such as m-chlorophenylpiperazine (m-CPP) and fenfluramine may induce migraine attacks. This has led to opposing theories concerning the role of 5-hydroxytryptamine (5HT) in triggering migraine attacks; is there hyperfunction or hypofunction of the central serotonergic system. Our review of the literature strongly suggests that m-CPP and fenfluramine provoke migraine attacks by stimulating, directly or indirectly, the 5HT_2C/5HT_2B receptors, although there is no total agreement with this interpretation. Central 5HT hypersensitivity in migraine patients, probably due to 5HT neuronal depletion, is proposed on the basis of review of electrophysiological tests and neuroendocrine challenge paradigms.     

Leukotriene B4 Generation by Polymorphonuclear Leukocytes: Possible Involvement in the Pathogenesis of Headache

SYNOPSIS
Leukotriene B₄ (LTB₄) levels in plasma and its generation in vitro from isolated polymorphonuclearleukocytes (PMN) were measured in migraine and cluster headache patients during and between painattacks. The LTB₄plasma levels in cluster headache patients during an attack were significantly higherthan in patients between attacks. There was a positive correlation between the time of sampling from thebeginning of attack and the LTB₄level. The LTB₄ plasma levels in migraine patients during and betweenattacks did not differ significantly from control levels. The results suggest that LTB₄appears rapidly in thecirculation at the beginning of a cluster attack and thereafter declines in amount. LTB₄release from PMNwas induced by stimulation with the calcium ionophore A23187. The release of LTB₄was significantlyhigher in migraine patients during attacks on stimulation with a submaximal dose of A23187 0.5 μM. LTB₄ release induced by A23187 in migraine patients during symptom-free intervals and cluster headachepatients did not differ from healthy controls. LTB₄ release was not affected by 5HT and NA inconcentrations up to 10^-4M. The results suggest that LTB₄is more easily generated in migraine patientsduring attacks. These studies on isolated cells provide a suitable model for the investigation of themetabolism of lipoxygenase derivates in headache patients.     

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.     

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.