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Abstract

Serotonin has long been implicated as a key neurotransmitter in migraine. There is a dearth of research specifically examining 5-HT1A receptor sensitivity in migraine despite the importance of this receptor in regulating central serotonergic tone. In this study we examined the hypothesis that migraine without aura is associated with hypersensitivity of central 5-HT1A receptors, using a 5-HT1A neuroendocrine challenge drug and comparing serum prolactin responses between a test group with migraine and a matched group of healthy controls.

Twelve female subjects fulfilling International Headache Society (IHS) criteria for migraine without aura were evaluated. Following an overnight fast, subjects presented for testing at 9am. An intravenous canula was inserted and serum prolactin was assessed at baseline and every 30 min for 3 h following a single dose of 30 mg oral buspirone, a 5-HT1A-receptor agonist. Subjects were assessed during the first 5 days of the menstrual cycle. No subjects were taking psychotropic medication or migraine prophylactic treatment. Patients with current or previous psychiatric disorder, daily headache or analgesic overuse were excluded. 16 healthy female volunteers matched for age and menstrual status were also evaluated and served as controls.

There was no difference in baseline prolactin between groups. There was a significant rise in prolactin following buspirone in both groups. Subjects with migraine had a significantly increased prolactin response to buspirone (delta max) compared to controls (P < 0.001).

This study supports the hypothesis that migraine without aura is associated with a relative hypersensitivity of central 5-HT1A receptors. This is of relevance given the role of the 5-HT1A receptor in controlling raphe 5-HT tone and in the possible association between migraine and anxiety and depression.

Keywords

Migraine serotonin 5-HT1A prolactin stress

Introduction

Ever since (1) reported that methysergide, a 5-HT antagonist prevented migraine headache, 5-HT has been implicated in the pathophysiology of the migraine syndrome. The main metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) is increased in the urine of migraine subjects during attacks (2). 5-HT releasing drugs such as reserpine and fenfluramine and the 5-HT agonist m-chlorophenylpiperazine have been found to induce headache in migraine subjects (3) and intravenous 5-HT itself has the potential to relieve migraine headache (4). Further support for the role of 5-HT in migraine comes from the observation that agents that treat the acute migraine attack (e.g. the triptan drugs sumatriptan, zolmitriptan) and also those that prevent migraine recurrence, (e.g. amitriptyline, pizotifen, methysergide) interact with 5-HT neurotransmission and/or receptors in the brain and in the periphery.

Abnormality in central 5-HT function in migraine has largely been inferred from animal models of head pain. However it is known that during the spontaneous human migraine attack there is an area of persistent activity in the region of the major monoaminergic nuclei (dorsal raphe nucleus (DRN); locus cerulus) of the brainstem (5). Stimulation of the periaqueductal grey (PAG) has serendipitously provoked migraine (6, 7) which lends further support to the importance of the 5-HT neurones of the DRN, in close proximity to the PAG, as a potential ‘migraine generator’. Positron emission tomography has also recently demonstrated increased central 5-HT synthesis capacity in migraine (8). The same authors have suggested that the enhancement of 5-HT synthesis capacity in migraine without aura but not migraine with aura, following treatment with propranolol, is attributable to the effects of propranolol at the 5-HT1A receptor. In the DRN, 5-HT1A receptors are largely located somatodendritically on 5-HT neurones where they function as autoreceptors regulating DRN 5-HT tone (9) and thus terminal 5-HT release from DRN projections. 5-HT1A receptor dysregulation could theoretically be associated with abnormal central 5-HT plasticity and a propensity towards migraine attacks but this hypothesis has not been tested.

It is well established that many migraine subjects have attacks, which are sensitive to life stress. Indeed migraine subjects may be particularly vulnerable to the effects of life stress (10). Migraineurs have a three-fold increased lifetime risk of both dysthymia and major depression (11) and the prevalence of anxiety disorders is also increased in migraine compared to the general population. The converse relationship also holds, i.e. that subjects with major depression have an increased lifetime risk of migraine (12). This bidirectionality of association suggests some shared pathophysiology between migraine and other stress disorders.

Disturbance in control of central 5-HT function may be the common pathophysiological mechanism, mediated at least in part by the 5-HT1A receptor. 5-HT1A receptor gene knockout mice have been developed and display high levels of stress susceptibility (13, 14). Agonists at the 5-HT1A receptor have been shown to have anxiolytic properties and at least one of these (buspirone), is used in clinical practice for the treatment of generalized anxiety (15). It has also been demonstrated that 5-HT1A receptor function is sensitive to stress via glucocorticoid mechanisms and that antidepressant treatment alters 5-HT1A receptor sensitivity (for review see16).

We therefore decided to investigate 5-HT1A receptor sensitivity in migraine using a neuroendocrine challenge paradigm. This paradigm utilizes hormonal response to 5-HT agonists as an index of central 5-HT receptor sensitivity. DRN projections to the hypothalamus are responsible in part for 5-HT-mediated hormonal release, via postsynaptic 5-HT receptors (17). That 5-HT is a major modulator of prolactin release is supported by the observation that drugs that stimulate 5-HT neurotransmission cause prolactin release from the anterior pituitary, an effect that may be prevented by pretreatment with 5-HT antagonists (18, 19). In rats, both inhibition of 5-HT synthesis as well as 5-HT receptor blockade have been shown to inhibit the prolactin response to suckling (20, 21). Buspirone, an azapirone that acts as an agonist at 5-HT1A receptors results in a robust release of prolactin in humans following acute ingestion (22). This response may be modified by 5-HT antagonist drugs, e.g. pindolol, a 5-HT1A antagonist (23) or methysergide, a nonspecific 5-HT antagonist (24). However, the neuroendocrine method of examining interictal central 5-HT receptor sensitivity has only rarely been examined in migraine with conflicting results (25, 26).

We hypothesized that subjects with migraine without aura would have 5-HT1A receptor hypersensitivity interictally (because of a relative depletion of 5-HT between attacks) compared to nonheadache control subjects. In order to avoid the potential confounding effects of gender, psychiatric morbidity, analgesic use and daily head pain on central monominergic function we examined a selected group of female subjects with migraine without aura.

Methods

Subjects

12 female subjects (age ± SE = 41 ± 4 years) with migraine without aura were recruited from the Beaumont Hospital Migraine/Headache clinic. All subjects gave written informed consent and the study was approved by the hospital ethics committee. Migraine without aura was operationally defined according to International Headache Society (IHS) criteria (27). All subjects had recurrent headache for at least 3 years and mean headache frequency was 12.6 ± 2.1 days with headache over the previous three months. Subjects were screened for psychiatric disorder using semistructered interview by a psychiatrist (EC). Subjects meeting DSM-IV criteria for major depression or any other psychiatric disorder (including chronic fatigue syndrome) were excluded from the study. Subjects also completed the Beck Depression Inventory and the Stait-Trait Anxiety Inventory. Subjects did not have any significant other medical disorder (including irritable bowel syndrome) and had not taken migraine prophylactic agents or psychotropic drugs in the previous 3 months. No triptan drugs or antiemetic drugs were taken for at least one week prior to the test and none of the subjects had headache less than 3 days prior to testing. Subjects with comorbid overuse of over-the counter analgesia or comorbid chronic daily headache were excluded. Subjects were also excluded if they had gained or lost more than 5% body weight within the previous month or were obese.

A control group of 16 healthy female volunteers (age ± SE; 40 ± 3 years) matched for age and menstrual status were also assessed.

Procedure

The study was conducted in Beaumont hospital according to a standardized procedure. Subjects were tested during the first 5 days of the menstrual cycle and during a migraine-free period. An indwelling 20-guage intravenous canula was inserted into an antecubital vein at 09.00 following an overnight fast. The subjects relaxed on a bed and were not allowed to eat or sleep for the duration of the test. After a resting period of 30 min, 2 baseline blood samples were taken 15 min apart. 30-mg oral buspirone hydrochloride was ingested by the subject at T⁰ and blood samples were taken every 30 min for 3 h. After oral buspirone, most migraine subjects and controls reported mild adverse effects. The most common side-effects were nausea, chills and light-headedness with predictable onset after 30–60 min and resolution after 120–180 min None of the subjects developed a headache during the test. Blood samples were collected into sterile serum tubes, centrifuged immediately and the decanted serum was stored at −20°C. Hormones were assayed using blinded batch analysis of serum prolactin by fluoroimmunoassay using commercially available kits (AutoDELFIA). The sensitivity of the prolactin assay was 1.44 mU/l. The intra-assay percent coefficients of variation (%CVs) were 2.2%, 3.1% and 1.6% and the interassay percentageCVs were 1.8%, 1.1% and 1.4%, respectively, for low (80 mU/l), medium (265 mU/l) and high (720 mU/l) controls.

Statistics

The statistical evaluation was performed using SPSS software. Values are expressed as mean ± standard error. Baseline serum prolactin (T⁰) was compared between groups using the student's t-test for independent samples. The prolactin response following buspirone challenge was calculated using ΔPRL values; that is, the maximum prolactin value minus the baseline prolactin. The t-test for independent samples was used to compare ΔPRL between groups. To examine whether possible covariates had any effect on change in prolactin between groups following buspirone, we used anova for repeated measures with time as the within-subjects factor, group (migraine or control) as the between-subject factor and baseline prolactin, state anxiety and depression as covariates. All tests of significance were 2-tailed and the level of statistical significance was taken at P < 0.05.

Results

Comparison of clinical data between groups

There was no significant difference in age (migraine: 41 ± 4.4 years compared to controls: 40 ± 3.4 years; P=0.8) or weight (migraine: 61.5 ± 1.8 kg compared to controls: 64.6 ± 2.4 kg; P = 0.3) between groups. Migraine subjects had more symptoms of anxiety (STAI-State anxiety: 36 ± 3.5 compared to 27.2 ± 2.4; P=0.06; STAI-Trait anxiety: 39.7 ± 5.8 compared to 26.8 ± 2.8; P=0.09) and depression (BDI depression: 10.9 ± 2.7 compared to 1.8 ± 0.8; P=0.01) than controls.

Comparison of baseline serum prolactin between groups

Although migraine subjects had lower baseline (T⁰) serum PRL than controls (231 ± 12.9 mU/l compared to 285.3 ± 22.7 mU/l), this was not significant (P = 0.07).

Comparison of serum prolactin response following buspirone between groups

The administration of buspirone induced a significant rise in serum prolactin from baseline in both migraine subjects (P < 0.001) and controls (P < 0.001), which was maximal 90 min after buspirone in both groups (Fig. 1). Migraine subjects had a significantly greater mean ΔPRL (1187.2 ± 179.8 mU/l) than controls (298.4 ± 33.8 mU/l) P < 0.001 (Fig. 2). Co-varying for baseline prolactin, state anxiety and depression did not affect these findings, i.e. there was a significant effect of time (F = 21.74; P = 0.002) and a significant group by time interaction (F = 12.89, P = 0.007).

Figure 1

Time course (in minutes) of rise in mean (± standard error) serum prolactin (mU/l) from baseline following buspirone challenge (at T⁰) in migraine without aura (•) and control (○) subjects. After covarying for baseline prolactin, depression and state anxiety, there was a significant effect of time (F = 21.74; P=0.002) and a significant group by time interaction (F = 12.89; P=0.007).

Figure 2

Comparison of mean (± 1SE) maximum rise in serum prolactin from baseline (ΔPRL) following buspirone challenge between migraine (without aura) and control subjects; P < 0.001 t-test for independent samples. For convenience, data is expressed as a percentage rise in serum prolactin from baseline.

Discussion

In this study we have demonstrated that female subjects who have migraine without aura have markedly exaggerated serum prolactin responses to the 5-HT1A agonist, buspirone compared to a well-matched control group. These results indicate that there is hypersensitivity of central 5-HT (1A) receptors in migraine without aura. It is difficult to attribute this altered 5-HT1A response to factors other than migraine given that confounding variables were controlled for.

Interictal central 5-HT receptor sensitivity has only rarely been examined in migraine by means of neuroendocrine tests. These tests have examined changes in serum prolactin, cortisol and growth hormone following pharmacological probes that interact with different 5-HT receptor types. Gordon et al. (25) found no difference in hormonal (cortisol and prolactin) responses to m-chlorophenylpiperazine (mCPP- 0.25 mg/kg) a 5-HT agonist drug, in eight subjects with migraine (with and without aura) and 10 normal controls. Cortisol and headache responses to mCPP, however, were highly correlated. There was no information on baseline hormonal values between groups and there was a male gender bias in controls. Males and females differ in their hormonal responses to 5-HT agonist drugs (28). The dose of mCPP may have been inappropriately low as suggested by the authors and the inclusion of both with and without aura subgroups reduces the power of the study.

Leone et al. (26) overcame some of these methodological problems. They found an increased maximal serum prolactin response to a higher dose of mCPP (0.5 mg/kg) in a group of 12 subjects with migraine without aura compared to 14 healthy controls. Although they excluded subjects with migraine with aura, there was a male gender bias in controls and female subjects do not appear to have been tested at specific stages of the menstrual cycle. Hormonal responses to 5-HT agonist drugs increase from early through mid-cycle to the luteal phase (22, 29), an effect which may be due to a priming of oestradiol on PRL synthesis, or 5-HT neurotransmission or both. Leone et al. (26) speculate that their finding is secondary to increased 5-HT1A-receptor sensitivity despite the preferential effect of mCPP at other 5-HT receptors (i.e. 5-HT1C receptor) (30).

Pinessi et al. (31) examined plasma growth hormone responses to subcutaneous sumatriptan, a 5-HT1B/1D agonist in a mixed group of male and female subjects with migraine with and without aura and a healthy control group. Subjects with anxiety or depression were excluded and controls were matched for age, gender and stage of the menstrual cycle. The authors found no difference in hormonal responses between groups and concluded that central 5-HT1D receptor sensitivity is normal in migraineurs between attacks. Sumatriptan, however, penetrates the blood–brain-barrier poorly and the hormonal responses to this agent therefore cannot be assumed to reflect central 5-HT receptor sensitivity. Sumatriptan is known to cause altered blood flow via its vasoconstrictor effects (32) and such an effect on pituitary blood flow might lead to hormonal release. In this regard it would have been helpful to measure release of other anterior pituitary hormones.

Two other frequently cited studies have evaluated 5-HT receptor sensitivity in migraine using fenfluramine, a 5-HT releasing drug. One study found no difference in prolactin responses compared to controls (33) whereas the other found an increased prolactin response in the migraine subjects indicating either 5-HT receptor hypersensitivity or increased 5-HT release (34). Neither study appears to have controlled for variables known to alter 5-HT responses.

Thus 5-HT challenge tests in migraine to date have yielded limited and conflicting information regarding central receptor sensitivity. This study attempts to overcome the methodological difficulties inherent in using these neuroendocrine challenge tests and indicates robust differences in 5-HT receptor sensitivity between migraine and control subjects.

The observed exaggerated prolactin release could reflect an enhanced pituitary prolactin reserve in migraine compared to control subjects. However, this is unlikely as there was no significant difference in baseline prolactin between migraine and control subjects in our study, a finding replicated elsewhere (35). Furthermore, prolactin release following thyrotrophin releasing hormone (TRH), a prolactin-releasing factor has yielded conflicting findings in migraine with evidence of both blunted (36) and exaggerated responses (37).

Exaggerated prolactin responses to buspirone challenge have been observed in other ‘somatic’ disorders which are associated with increased susceptibility to mood disturbance, e.g. chronic fatigue syndrome (38) and nonulcer dyspepsia (39) suggesting that this finding is marker for trait stress vulnerability.

If the 5-HT1A receptor were an important mediator of susceptibility to migraine attacks one might expect some migraine prophylactic agents to have efficacy at the 5-HT1A receptor. The most effective migraine prophylactic agents (i.e. propranolol, pizotifen, valproate, amitriptyline, methysergide, and lisuride) interact with central 5-HT receptors. Methysergide, a nonselective 5-HT antagonist inhibits 5-HT-mediated behaviour (40) and the prolactin response to restraint in rats (41) as well as the hormonal response to head-up tilt in humans (42). Pizotifen and amitriptyline attenuate the hypothermic response to the 5-HT1A agonist 8-OH-DPAT, a 5HT1A autoreceptor-mediated effect (43, 44). Valproate induces prefrontal DA by stimulating 5-HT1A receptors in rats (45) and in humans chronic treatment with valproate inhibits the hypothermic response to the selective 5-HT1A agonist ipsapirone (46). Lisuride also induces 5-HT1A mediated behaviours, which may be prevented by 5-HT1A-receptor blockade (47). Propranolol alters 5-HT synthesis capacity in migraine subjects, an effect which may be mediated by 5-HT1A receptors (8). Thus, migraine prophylactic drugs may act to prevent migraine attacks in part by stabilizing central 5-HT1A receptor function.

Conclusion

These results indicate that migraine without aura subjects have hypersensitivity of central 5-HT (1A) receptors. We hypothesize that the 5-HT1A receptor plays a crucial role in regulation of central 5-HT function and therefore susceptibility to both migraine attacks and mood disturbance following life stress. Future studies in progress will clarify whether our finding can be generalized to other migraine subtypes and whether comorbidity of daily headache, analgesic overuse and depression has any effect on function of the 5-HT1A receptor.

Footnotes

Acknowledgements

This work was funded in part by the Irish Brain Research Organization and the Migraine Association of Ireland.

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Central 5-Ht Receptor Hypersensitivity in Migraine Without Aura

Abstract

Keywords

Introduction

Methods

Subjects

Procedure

Statistics

Results

Comparison of clinical data between groups

Comparison of baseline serum prolactin between groups

Comparison of serum prolactin response following buspirone between groups

Discussion

Conclusion

Footnotes

Acknowledgements

References