Serotonin and migraine: a reconsideration of the central theory

The evaluation of 5-HT reactivity in hand vein in a large sample shows that migraine subjects are more sensitive to controls. Moreover, female migraineurs are more sensitive than male migraineurs (Fig. 1). Higher 5-HT sensitivity in females was also found in other human vascular districts such as mammary and radial arteries [38, 39]. Interestingly, a heritable sexual dimorphism was described for whole blood 5-HT levels with higher level in women compared with men [40].

Important gender differences exist also in human brain 5-HT neurotransmission [41, 42], different to those with animal studies [43]. Studies of cerebrospinal fluid (CSF) concentrations of 5-HIAA, indirect indices of 5-HT synthesis and, by implication, of the transmitter for release into the synaptic cleft have yielded inconsistent results (see [42]). However, 5-HIAA reflects other processes in addition to 5-HT synthesis.

Validated positron emission tomography (PET) studies showed that men synthesize 5-HT significantly faster than women, and also with left-to-right differences [42, 44] even if an inverse finding was reported in a small study [45]. These gender differences are found in cortical regions but not in sub-cortical structures, including brainstem, where most 5-HT cell bodies are found [42]. Acute tryptophan depletion (ATP) causes a larger decrease in the rate of 5-HT synthesis in women [44]. It was affirmed that human males and females seem to have similar stores of brain 5-HT, but if there were increased utilization of 5-HT during stressful situations, a lower rate of synthesis in the females may not be as efficient in maintaining adequate stores of the neurotransmitter and then in such situations the 5-HT level would decline more in females [44]. Healthy women were reported to have higher 5-HT transporter availability in the diencephalon and brainstem compared to men. Since the 5-HT transporter functions to regulate 5-HT neurotransmission, these findings tend to suggest that baseline 5-HT functions may be higher in women versus men. Women have also higher number of 5-HT_1A receptors but not of 5-HT_2A: the latter are, however, increased by estrogens (see [41]). The greater (upregulation) 5-HT_1A bindings may be consequence of lower activity (synthesis) of serotonergic system (see [42]). Estrogens and estrogens + progesterone (that is the reproduction of the hormonal cycle of females) act on the gene and protein expression in dorsal raphe nucleus of non-human primates in a manner that suggests that 5-HT neurotransmission should increase: reduction of 5-HT_1A, decrease 5-HT reuptake transporter (SERT), increase of tryptophan hydroxylase, MAO-A inhibition. The direct evidence of steroid-induced 5-HT release was sought with microdialysis [46].

The evaluation of seasonal changes in the vascular 5-HT hand vein reactivity clearly shows a lesser 5-HT sensitivity in the summer (Fig. 2). Many clinical studies, conducted in Italy and Austria, show that migraine frequency is lower in the summer in comparison to winter or autumn [47‐52] (Table 3). Other studies do not concord [49, 50]. However, in one of these [50], when a bias was corrected, the seasonal differences disappeared, and even if real the seasonal effect is weaker. Also the reported higher attacks of migraine with aura (but not without aura) in the light season compared to the dark season in the arctic area became insignificant when insomnia-related attacks were removed [53]. In spite of this, in this latter study the peak frequency of migraine without aura was in December and the lowest frequency in June.

There are many evidences of increased content/turnover of 5-HT associated to decreased 5-HT receptor sensitivity in the brain, and also of plasma and platelet 5-HT content in the summer [1, 54].

The amount of 5-HT and its metabolites in the CSF are, at best, an imprecise indicator of brain serotonergic neuronal activity (synthesis). The measure of the differences between concentrations of neurotransmitters in the arteries and the internal jugular vein permit us to estimate the amounts produced in the brain. With this technique it was shown that in man, 5-HT turnover was lowest in winter and highest in summer, and was correlated to the bright sunlight of the day [55]. This finding was selective because extracerebral 5-HT turnover and also brain turnover of norepinephrine and dopamine did not show any seasonal variation. Another interesting preliminary finding is the reduced brain SERT availability in the winter compared to the summer [56].

About 25 years ago, it was proved that migraine patients usually do not show tachyphylaxis (habituation) to the vasoconstrictive activity of 5-HT, different to control subjects [57].

Later on, the lack of habituation was thought to be the principal interictal abnormality in sensory processing in migraineurs, hypothesized due to hypofunction of 5-HT pathway to the thalamus and cortex [58‐62]. Normalization of habituation during the attack was found [22, 63, 64] with a parallel decrease of platelet 5-HT [22]. According to Evers [22] the lack of significant association between the amount of habituation and platelet or plasma 5-HT suggested that the habituation phenomenon cannot be attributed to 5-HT neurotransmission; however, central 5-HT modification cannot be excluded.

Although the phenomenon of reduced habituation in migraineurs has been investigated mainly in the central nervous system, there are examples even in the peripheral system [65‐67].

A single dose of reserpine will consistently induce headaches, closely resembling migraine, when administered intravenously, intramuscularly, or subcutaneously; but not or rarely in healthy controls [68]. Also fenfluramine provokes headache in more than 50% of migraine patients, with a mean latency of 4.5 h, which was suggested to be due to 5-HT depletion, but not or less frequently in control subjects [65, 69]. However, the hypothesized 5-HT neuronal depletion as a mechanism of induced-headache apparently contrasts with some reports showing that chronic treatment with these two drugs, which probably provokes more depletion than acute treatment, and with the prototype of the depleting drugs p-chlorophenylalanine (PCPA), can have therapeutic effect on some migraine patients [69‐71]. Fenfluramine challenge test administered to healthy subject (no migraine sufferers), provoked side effects in 90% of cases during the day, but more than half the following day: headache/migraine account of 43% of cases [72].

The 5-HT_2C receptor agonist mCPP is the most extensively used probe to show an altered serotonergic neurotransmission in migraine.

Brewerton et al. [73] reported that mCPP provoked severe headaches with migraine features 6-12 h after a single oral dose (0.5 mg/kg) in about 50% of female subjects. The incidence of headache was significantly greater in subjects with a personal or family history of migraine. Headache response following mCPP is greater in female patients with bulimia nervosa than control, irrespective of a personal or family history of migraine [74]. Another study tested on a few subjects, predominantly men, reported that mCPP (0.25 mg/kg) induced headache in 50% of subjects, but without differences between migraine patients and controls, with a mean time onset of 5.3 h [75]. The induction of migraine-like headache in some subjects without personal history of migraine was also reported during pharmacokinetics studies, 5–10 h after oral administration [76]. However, that mCPP provokes more migraine (according to International Headache Society classification) than placebo and more likely in migraine patients than in controls was more recently confirmed [77].

The headache rating and duration was correlated with plasma peak concentration of mCPP occurring several hours earlier, and with the area under the curve (AUC), without differences between migraine and controls [73‐75, 77], but no relation with plasma level was also reported [76]. Large inter-individual differences in mCPP pharmacokinetic parameters were shown [76, 78]. Interestingly, the AUC after oral administration varied more than 40-fold, was threefold higher than intravenous administration, reached their peak after more than 3 h, and could still be measured after 8 h, and no differences were seen between male and females [76].

The fact that there were no differences in the cortisol response to mCPP between migraine patients and controls had led to the suggestion that 5-HT_2C receptors are normal in migraine [75, 79]. Prolactin response was shown to be both normal [75] and increased [79]. The peak of these neuroendocrine responses was at 90–150 min, and both correlation [75, 79], and non-correlation [78] with mCPP plasma concentrations were reported. Also some subjective side effects, other than headache, occur within 3 h [78]. The fact that hormonal response precedes the headache suggests that mCPP interaction with 5-HT receptors in the brain occurs initially in the cascade of events that ultimately results in headache [75], or that headache is not due to direct 5-HT receptor stimulation. Moreover, whether 5-HT receptor sensitivity is decreased or increased probably depends on the anatomical location of the pathway mediating the target response, and differential involvement of 5-HT receptor subtype. In fact, mCPP in addition to its 5-HT receptoral agonist activity is similar to fenfluramine, a potent 5-HT releaser [80]. This property should be taken into account for the similar time latency in the headache provocation shown by these two drugs.

However, for its adverse side effects and its variability of pharmacokinetic and of clinical and hormonal effects, m-CCP was suggested to be an inadequate drug to carry out challenge tests to test receptor sensitivity in vivo [78].

The 3,4-methylenedioxymethamphetamine (MDMA/ecstasy) is an illicit drug that stimulates the release of 5-HT from neurons [80]. Although systematic studies have not been performed to show headache provocation, a comprehensive review of studies on the acute subjective effects of MDMA shows that not only headache, but also nausea and vomiting, is one of the more frequently reported somatic effects [81].