Serotonin and Migraine: The Latest Developments

Abstract

There is a significant body of evidence implicating serotonin (5-HT) and its receptors in the pathophysiology of headache. The majority of evidence is derived from studies showing altered concentrations of serotonin and its metabolites in subjects with headache and from recognition of the treatment effects of serotonergic medications. Serotonin is considered to play a role in multiple headache types including migraine with aura, migraine without aura, menstrual migraine and medication overuse headache.

Serotonin acts mostly as an inhibitory neurotransmitter. The 5-HT1 receptor family, including the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F receptors, mediates pre- and postsynaptic inhibition. Immunoreactivity to 5-HT1B receptors is present on the cerebrovasculature, whereas 5-HT1D immunoreactivity is present on trigeminal nerve endings (1–3). Excitatory effects of serotonin are mediated by 5-HT3 receptors, which play a role in nociception and vomiting. Serotonin can have varying effects on vessel tone, causing either vasodilation or vasoconstriction. Vasoconstriction is mediated by receptors in the 5-HT1 and 5-HT2 families.

The serotonin transporter (SERT) is responsible for presynaptic reuptake of serotonin and thus regulates the concentration of serotonin at the synapse. Drugs such as the selective serotonin reuptake inhibitors have high specificity for blocking serotonin reuptake by SERT. Serotonin is broken down by monoamine oxidase to make 5-hydroxyindolacetic acid (5-HIAA).

There have been multiple studies of the serotonergic system in migraine. Although there have commonly been contradictory results, the following trends have been noted:

Serotonin levels in the plasma are altered in subjects with migraine. Interictally, 5-HT levels are lower, whereas 5-HIAA levels are higher than in non-migraine controls. During migraine attacks, 5-HT levels increase, whereas 5-HIAA levels decrease (4).

There is a reduction in platelet serotonin concentration during migraine without aura attacks (4, 5). Platelets are the main repository of serotonin in the blood. A similar reduction has not been demonstrated during migraine with aura.

There is an increase in 5-HIAA concentrations in the urine during migraine attacks (6).

There is increased brain serotonin synthesis in patients with migraine (7). 5-HIAA concentrations are elevated in the cerebrospinal fluid of migraine patients, suggesting increased breakdown of serotonin in the central nervous system (8).

Although these are possible trends, there is a significant amount of conflicting data in the literature. Thus, it is difficult to draw absolute conclusions in regards to concentrations of serotonin and its metabolite in subjects with migraine. However, the majority of available evidence points towards a systemic disturbance of serotonin metabolism in patients with migraine (9).

Further implicating serotonin as a player in migraine, many of the medications used for acute and prophylactic treatment have actions on the serotonergic system. The triptans are selective 5HT-1B, D (F) agonists which treat migraine via neuronal and vascular effects along the trigeminal vascular system. Cerebral vasoconstriction is mediated through the 5-HT_1B receptor subtype (2). Inhibition of vasoactive neuropeptide release, neurogenic inflammation, and firing of trigeminal afferents is mediated by agonistic activity at 5-HT_1D and 5-HT_1F receptors (10, 11). Ergotamine and dihydroergotamine abort migraine attacks via their action as agonists at 5-HT1B and 5-HT1D receptors as well as noradrenergic and dopamine receptors. In addition, many migraine prophylactic drugs have serotonergic effects. Examples include: methysergide, pizotifen, cyproheptadine, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors and propranolol.

There is overwhelming evidence to suggest a role for the serotonergic system in migraine. However, there is still much to be learned in order to define this role further. The following text contains summaries of and commentary on five manuscripts which have been published in the last 2 years and are felt to add significantly to our understanding of the function of serotonin and its receptors in migraine.

1. Berman NEJ, Puri V, Chandrala S, Puri S, Macgregor R, Liverman CS, Klein RM. Serotonin in trigeminal ganglia of female rodents: relevance to menstrual migraine. Headache 2006; 46:1230–45

Objective

To study the trigeminal ganglia of female mice to determine which components of the serotonin system are present. To determine if there are changes in expression of genes related to the serotonin system during different stages of the oestrous cycle.

Methods

C57/BL6 mice aged 6–8 weeks were used for study. Stage of oestrous cycle was determined by studying cells obtained from vaginal lavage for at least 15 consecutive days. Mice were studied during pro-oestrus, early oestrus and dioestrus. Reverse transcriptase-polymerase chain reaction was used to study gene expression and Western blot was used to examine protein expression. Neurons were identified using double-label immunohistochemistry and confocal microscopy. Tissue cultures were employed to study the effects of oestrogen on trigeminal neurons.

Results

At high oestrogen states (pro-oestrus) mRNA levels of tryptophan hydroxylase (TPH) were 2.2 times higher than at dioestrus (P = 0.03). TPH protein levels in the trigeminal ganglia were 1.4 times higher at pro-oestrus than dioestrus (P = 0.014). However, trigeminal cultures treated with β-estradiol did not demonstrate increased amounts of TPH-1 protein. Expression of 5HT-1B and 5HT-1D did not significantly change with different stages of the oestrous cycle. Colocalization of serotonin and 5HT-1B on trigeminal nociceptors showed that 70% of serotonin- positive neurons contained 5HT-1B and 41% of 5HT- 1B-positive neurons contained serotonin.

Conclusions

This study has shown that serotonin and TPH are present in trigeminal ganglia of female mice. Levels of TPH mRNA and protein were higher during high oestrogen phase of the oestrous cycle. 5HT-1B and 5HT-1D are expressed in trigeminal ganglia, but this expression does not change with the oestrous cycle. Serotonin was present in about one-half of all trigeminal neurons, many of which contained 5HT-1B.

Commentary

Dr Berman and colleagues received the prestigious Harold G. Wolff Award for this important work regarding serotonin, the trigeminal ganglia, and menstrual migraine. This study was able to demonstrate the presence of serotonin and its rate-limiting enzyme, TPH, in trigeminal neurons of mice. It suggests that TPH and serotonin-containing axons, which are found in several cerebral structures, originate in the trigeminal ganglia. Consistent with prior studies, 5-HT1B and 5HT-1D receptors were present in trigeminal neurons. Serotonin-containing neurons were present in all subtypes of trigeminal neurons, including nociceptive and non-nociceptive sensory neurons. This included calcitonin-gene related peptide (CGRP)-containing neurons, nociceptive neurons with peptides other than CGRP, and neurons with myelinated and unmyelinated axons. Colocalization was significant between serotonin and 5HT-1B receptors in mice trigeminal neurons. This suggests that 5HT-1B receptors may act as autoreceptors, inhibiting the release of serotonin from trigeminal axon terminals. 5HT-1B receptor presence on trigeminal neurons that do not contain serotonin suggests that these receptors may also act as heteroreceptors. Thus, agonists of this receptor at the trigeminal neuron may have the ability to decrease the release of other substances involved in migraine such as CGRP.

This study lends several important findings related to menstrual migraine. The expression of 5HT-1B and 5HT-1D receptors did not differ through the oestrous cycle. Thus, receptor expression may not play a significant role in defining the relationship between oestrogen states and migraine. However, levels of TPH were shown to be hormonally regulated. TPH levels were significantly increased during pro-oestrus, the high oestrogen stage, compared with dioestrus, the low oestrogen stage. Thus, TPH may be found in higher concentrations in females than males, and changing levels across the menstrual cycle may contribute to menstrual migraine. As the authors state, further studies of the TPH-1 gene are indicated, as this gene may play a role in migraine pathogenesis.

2. Shields KG, Goadsby PJ. Serotonin receptors modulate trigeminovascular responses in ventroposteromedial nucleus of thalamus: a migraine target? Neurobiol Dis 2006; 23:491–501

Objective

To determine if the triptans, 5-HT1 receptor agonists, act upon cells in the ventral posterior medial (VPM) nucleus of the thalamus.

Methods

Trigeminal afferents innervating the superior sagittal sinus (SSS) of anaesthetized male Sprague-Dawley rats were stimulated with platinum wire electrodes. Extracellular recordings were made from neurons in the region of the VPM nucleus of the thalamus. Receptive fields were identified on the contralateral craniofacial region and used to classify cells as low-threshold mechanoreceptive, nociceptive specific or wide dynamic range. l-glutamate was microiontophoretically applied at a rate that yielded a sustainable firing rate comparable to the response elicited by stimulation of each cell's receptive field. The effect of serotonergic agonists was tested by their application with l-glutamate and compared with control. Naratriptan was microiontophoretically and intravenously applied. The affect of naratriptan administration on SSS stimulation was measured. The response of each cell under three test conditions was studied: (i) l-glutamate (baseline); (ii) l-glutamate co-ejected with control (Na+); and (iii) l-glutamate co-ejected with 5-HT agonist. Additional studies were performed using a 5HT1B/D antagonist. In these studies, the response of each cell was measured: (i) at baseline; (ii) with antagonist; (iii) with naratriptan; and (iv) with antagonist and naratriptan.

Results

A total of 48 cells from the VPM thalamus were studied. Twenty-nine were vibrissal, 11 were low threshold mechanosensitive, seven were wide dynamic range, and one was nociceptive specific. Microiontophoretic injection of naratriptan reversibly reduced cell firing in response to SSS stimulation (n = 8, t₇ = 5.5, P = 0.001) in comparison to control (n = 8, t₇ = 1.7, P = 0.1). Intravenous naratriptan inhibited SSS stimulation (n = 8, t₇ = 13.3, P < 0.001) compared with baseline. Microiontophoretic ejection of naratriptan reversibly suppressed l-glutamate-evoked firing in all cells tested (n = 9, F _1,4 = 35, P < 0.001). Co-ejection of 5-HT1 receptor antagonists (5-HT1A/B/D) with naratriptan partially antagonized the effect of naratriptan on l-glutamate-evoked cell firing. Ergometrine maleate also inhibited cell firing from l-glutamate ejection (n = 6, F _1,4 = 41, P = 0.001).

Conclusions

This study demonstrates a serotonergic, 5-HT1 receptor-mediated inhibition of neurons in the VPM nucleus of the thalamus. Naratriptan inhibits trigeminovascular transmission in the thalamus initiated by electrical stimulation of the SSS. This effect is largely due to its action at 5-HT1A, 5-HT1B and 5-HT1D receptors. Ergometrine had a similar effect.

Commentary

These studies by Shields and Goadsby have implications for our basic understanding of the physiology and treatment of migraine. Although certainly presumed to play a role in the neurobiology of migraine, the thalamus has not been extensively studied in this regard. The majority of research studying the effects of migraine medications has focused on the more caudal trigeminovascular system and inhibition of neurogenic inflammation. However, therapeutic effects on structures such as the thalamus and sensory cortex are largely unknown. These studies demonstrate that naratriptan and ergometrine maleate inhibit activity in the VPM nucleus of the thalamus, probably via their activity at serotonin receptors. It was also found that 5HT-1B/D receptors affected postsynaptic activity in response to l-glutamate ejection. This finding is of interest, because these receptors have been thought to be present mostly on presynaptic terminals. However, this suggests that 5HT-1B/D receptors are also present on the postsynaptic membrane or that presynaptic receptors have the ability to modulate postsynaptic action potentials.

In addition to enhancing understanding of the mechanisms by which migraine medications work, further study of how the thalamus processes nociceptive input from the trigeminovascular system will lend important insights into our basic understanding of migraine. Abnormal central processing of sensory input, perhaps at the level of the thalamus, may play an important role in the pain, photophobia and phonophobia of migraine. Prior studies have suggested that the thalamus plays a role in migraine. Hyperperfusion of the thalamus during spontaneous attacks of migraine has been documented (12). Thalamocortical activity is reduced in patients with migraine interictally (13). Other studies have implicated specifically the VPM nucleus of the thalamus in migraine. Electrical stimulation of the superior sagittal sinus has been shown to result in a 188% increase in metabolic activity in the VPM thalamus without significant changes in the surrounding thalamus. This response is blocked by bilateral trigeminal ganglion ablation (14). Previous work by Shields and Goadsby has shown that, like naratriptan's action at the VPM thalamus, propranolol may exert some of its beneficial effects on the prevention of migraine via β₁ adrenoceptor antagonism in the VPM thalamus (15). These studies have provided convincing evidence that the thalamus, probably the VPM nucleus of the thalamus, is part of the ascending pathway in migraine. However, studies are required to investigate whether the thalamus simply acts as a relay station for altered sensory input or if it plays a role in producing these alterations in migraine. If thalamic processing of sensory input from the trigeminovascular system is altered in migraine, more intensive study of this structure will be required to understand migraine and its treatments.

In addition to the effects of triptans on the 5-HT1 receptors themselves and the neurovasculature, these studies show effect on VPM neurons. These results support and confirm the multifaceted effects of the triptans for the treatment of migraine. Just as migraine itself is a complicated multimodal disease, effective treatments for migraine are likely to exert their effects at multiple points along the migraine pathway. Modulation of thalamic processing of trigeminovascular nociceptive input to the sensory cortex could be an effective method by which to treat migraine headache.

3. Supornsilpchai W, Sanguanrangsirikul S, Maneesri S, Srikiatkhachorn A. Serotonin depletion, cortical spreading depression, and trigeminal nociception. Headache 2006; 46:34–9

Objective

To study the effect of serotonin depletion on the propensity to cortical spreading depression and thus on cortical spreading depression triggering of trigeminal nociception.

Methods

Control group Wistar rats were compared with rats who had 5-HT depleted by administration of a tryptophan hydroxylase inhibitor. Potassium chloride was applied to the parietal cortex of all rats to induce cortical spreading depression. Cortical activity was measured for 1 h after administration of potassium chloride. The number, amplitude, duration and area under the curve of cortical spreading depression waves were measured. Trigeminal nociception was determined by examining the expression of Fos in the trigeminal nucleus caudalis.

Results

The number of cortical spreading depression waves was greater in the rats with low serotonin levels (14 ± 2 vs. 11 ± 1, P = 0.001). The area under the curve was greater in the low serotonin rats (73.11 ± 11.42 vs. 58.99 ± 10.01, P = 0.020). There was no difference between groups as regards the amplitude and duration of cortical spreading depression waves. The number of Fos-immunoreactive cells detected on the ipsilateral and contralateral trigeminal nucleus caudalis was greater in the low serotonin rats than in the controls (ipsilateral: 46 ± 12 cells per slide vs. 29 ± 2 cells per slide, P = 0.002; contralateral: 26 ± 5 cells per slide vs. 8 ± 2 cells per slide, P = 0.015).

Conclusions

Serotonin depletion increases excitability of the cerebral cortex and the sensitivity of the trigeminal nucleus caudalis. Thus, serotonin depletion predisposes to cortical spreading depression-induced trigeminal nociception.

Commentary

This study increases our knowledge regarding propensity to cortical spreading depression. The authors have shown that rats with low serotonin levels had an increased number and size of cortical spreading depression waves after administration of potassium chloride. This suggests that low serotonin levels predispose to migraine aura. This could also have implications for migraine without aura if cortical spreading depression is found to be a wider phenomenon in this group (16, 17). It has been proposed that cortical spreading depression not only is the physiological substrate of migraine aura, but also leads to activation of the trigeminovascular system and thus to the pain of the migraine.

This study provides a mechanism by which low serotonin levels could predispose to migraine. As previously discussed, low interictal levels of serotonin in the blood have been found in patients with migraine. However, our understanding of the mechanisms by which low serotonin levels may be associated with migraine has been speculative. It has been suggested that low serotonin concentrations may lower pain perception thresholds and adversely affect the control of cerebrovascular nociception. This study shows that low levels predispose to cortical spreading depression. Human studies that associate low serotonin levels with propensity to cortical spreading depression are necessary to confirm these findings.

4. Schuh-Hofer S, Richter M, Geworski L, Villringer A, Israel H, Wenzel R, Munz DL, Arnold G. Increased serotonin transporter availability in the brainstem of migraineurs. J Neurol 2007; 254:789–96

Objective

To use brain serotonin transport protein (SERT) radioligand and single photon emission computed tomography (SPECT) imaging to determine if the mesopontine serotonergic system is involved in the pathophysiology of migraine.

Methods

Nineteen subjects with migraine (17 without aura, two with aura) and 10 healthy, age- and sex-matched controls were enrolled. Magnetic resonance imaging (MRI) was performed in order to define regions of interest for SPECT images. SERT radioligand, ¹²³I-ADAM, was injected intravenously. SPECT was then performed and MRI and SPECT images were co-registered. The brainstem region of interest consisted of the mesencephalon and pons. Uptake of ligand was assessed at the mesopontine brainstem, the thalamus and the occipital lobe. The occipital lobe was used as the reference region for assessing counts in the regions of interest (region of interest—reference region/reference region). Two-tailed Student's t-test and linear regression analysis were used to test for significant differences between groups.

Results

¹²³I-ADAM uptake was significantly higher in the brainstem of subjects with migraine (0.88 ± 0.16) compared with healthy controls (0.58 ± 0.20, P < 0.001). Uptake in the thalamus of subjects with migraine was 0.92 ± 0.38 compared with 0.7 ± 0.17 in healthy controls (P = 0.09). Linear regression analysis performed for individual monthly migraine days and mesopontine SERT availability yielded r = 0.5, P = 0.027. Regression analysis of disease duration and radioligand uptake yielded r = 0.06, P = 0.79.

Conclusions

SERT availability in the mesopontine brainstem of subjects with migraine is increased compared with healthy controls. Although there was a trend towards an increase in the thalamus of subjects with migraine, the difference did not reach statistical significance. A mild positive correlation between monthly migraine days and ¹²³I-ADAM uptake in the mesopontine brainstem was found. There was no correlation between number of years with migraine and radioligand uptake.

Commentary

The use of radioligands to study the pathophysiology of migraine allows for study at the neurotransmitter level. The serotonin transporter (SERT) has an essential role in the transmission of serotonin in the nervous system, as it is responsible for the uptake of serotonin from the synaptic cleft. ¹²³I-ADAM, a SERT radioligand, has been shown to have high specificity for its binding to SERT (18). Therefore, SPECT imaging using this tracer is a valuable method for studying potential alterations in the central neurotransmission of serotonin in subjects with migraine.

The spatial resolution of the technique used in this study allowed for study only of relatively large regions of interest. Thus, increased radioligand uptake could be localized to the mesopontine brainstem but not to specific structures within this region. As the authors note, there are several structures in the mesopontine brainstem which are involved in the regulation of pain, including dorsal raphe nucleus, locus ceruleus, parabrachial area, reticular formation and the periaqueductal grey.

In addition, it is not possible to determine if the increased availability of SERT is a causal factor for migraine or a secondary effect of migraine. The finding of an association between the frequency of headaches and increased SERT availability may suggest that the increased availability is secondary to the migraine state. The direction of this association may be better defined by studying larger numbers of patients and using subjects with pain types other than migraine headache.

Despite its limitations, this is an important early study using a radioligand tracer and SPECT to examine a component of serotonergic transmission in the brain of subjects with migraine. Hopefully, this will lead to future studies that may correlate SERT availability with serotonin concentrations. There is evidence that changes in SERT do affect serotonin concentrations. Studies in SERT knockout rat models have shown that serotonin homeostasis is significantly affected in SERT(–/–) rats. In such rats, serotonin tissue levels and depolarization-induced serotonin release were significantly reduced. In addition, SERT knockout does not seem to cause changes in non-serotonergic systems such as dopamine, noradrenaline, glutamate and GABA (19). Using SPECT imaging and ¹²³I-ADAM to study other headache types and other pain states will help to determine the specificity of this study's findings to subjects with migraine.

5. Zhang X, Strassman AM, Burstein R, Levy D. Sensitization and activation of intracranial meningeal nociceptors by mast cell mediators. J Pharmacol Exp Ther 2007; 322:806–12

Objective

To determine which mast cell-derived mediators activate and promote sensitization of meningeal nociceptors.

Methods

This study employed single-unit recordings of meningeal nociceptors in the trigeminal ganglia of anaesthetized male Sprague-Dawley rats. Mechanical receptive fields of meningeal nociceptors were mapped by mechanical stimulation of the dura. Baseline mechanical thresholds were determined using von Frey filaments and quantitative measurement of response magnitudes. Histamine, serotonin, prostaglandin D₂ (PGD₂)_, Iloprost (PGI₂ stable analogue) and leukotriene C₄ (LTC₄) were individually applied to the dural receptive field. Individual neurons were tested with increasing doses of each mast cell mediator while neuronal activity was recorded. For each neuron, increases in threshold, suprathreshold and ongoing discharge level were defined as an increase in firing rate that exceeded the baseline mean plus two times the standard deviation of the mean. Effects on A-delta and C-units were analysed separately.

Results

Histamine application resulted in increased threshold and suprathreshold responses in 7/10 C-units and 2/9 A-delta units tested. Histamine-induced mechanical sensitization was short-lived, with return to baseline sensitivity at 15 min after wash-out. Ongoing discharge rate was increased in 6/10 C-units and 1/9 A-delta units. PGI₂ resulted in increased threshold responses in 4/6 A-delta units and 5/7 C-units. Increased suprathreshold response was seen in only 1/6 A-delta units and 1/7 C-units. The level of ongoing discharge was increased in 3/6 A-delta and 5/7 C-units. PGD₂ evoked only a minimal sensitization in 1/6 A-delta and 1/6 C-units and had only a minimal effect on spontaneous activity in 1/6 C-units. LTC₄ did not affect mechanical sensitivity or spontaneous activity in any of the meningeal nociceptors. Serotonin increased threshold responses in 4/6 A-delta units and 7/8 C-units. It increased suprathreshold responses in 5/6 A-delta units and 5/8 C-units. In most sensitized neurons, responses remained increased for 30–45 min during the last wash-out period. Serotonin increased spontaneous activity in 4/6 A-delta and 5/8 C-units. Increased spontaneous activity persisted for at least 30 min during the last wash-out period.

Conclusions

Mast cell mediators may activate and sensitize meningeal nociceptors to mechanical stimulation. Of the mediators tested, serotonin, PGI₂ and, to a lesser extent, histamine activated these nociceptors. Serotonin was the most potent mediator, affecting both activation and mechanical sensitization of threshold and suprathreshold responses in A-delta and C-units. Thus, the authors propose that in conditions where mast cells are activated during a migraine attack, serotonin, PGI₂ and histamine may play a role in promoting the pain.

Commentary

Although the majority of serotonin in the blood is found in platelets, a significant amount is also found in the granules of mast cells. Mast cells are found in the dura of humans, near blood vessels and meningeal nociceptive neurons (20). This study shows that serotonin, a mast cell mediator, plays a role in the activation and mechanical sensitization of meningeal nociceptors. Of the mast cell mediators tested in this study, serotonin was the most potent. It was shown to promote activation and sensitization in both C and A-delta meningeal nociceptor populations.

Prior work has linked mast cell degranulation with migraine headaches. Animal studies have shown that electrical stimulation of the trigeminal ganglion leads to activation of meningeal nociceptors and thus degranulation of dural mast cells (21, 22). During migraine with aura, cortical spreading depression is thought to activate meningeal nociceptors, which then release vasoactive neuropeptides. These vasoactive neuropeptides, such as CGRP and substance P, cause degranulation of dural mast cells (23). This process of neurogenic inflammation is felt to result in further activation and sensitization of meningeal nociceptors. In addition, it has been recently demonstrated that mast cell degranulation can cause prolonged activation of neighbouring trigeminal meningeal nociceptors (24). However, from that study it was unclear which mast cell mediator(s) is responsible for this effect on meningeal nociceptors. The study by Zhang and colleagues that is abstracted here helps to answer this question. Serotonin, PGI₂ and histamine (to a lesser degree) were found to activate these meningeal nociceptors.

These studies have also lent insights into the mechanism of action of the triptans. In addition to its effects on meningeal nociceptors, mast cell degranulation has been shown to cause activation of nociceptive neurons in the trigeminal nucleus caudalis (24). Sumatriptan has been thought to exert some of its antimigraine effects via inhibition of mast cell degranulation (25). Studies by Levy and colleagues have demonstrated that sumatriptan prevents the induction of sensitization in central trigeminovascular neurons, but not in meningeal nociceptors (24, 26) After sensitization is established, sumatriptan can normalize intracranial hypersensitivity of central neurons, but fails to do so in peripheral neurons. The authors concluded that sumatriptan prevents the development of central sensitization and terminates migraine by blocking synaptic transmission between peripheral and central trigeminovascular neurons without inhibiting activation and sensitization of peripheral meningeal nociceptors. In addition to better understanding the mechanism of action of sumatriptan, this finding serves as additional evidence for an interaction between mast cell degranulation and activation of the trigeminovascular system.

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