Dopamine and Migraine: Trigeminovascular Nociception,Genetics and Therapeutics

INTRODUCTION

This year marks the thirtieth anniversary of Professor Federigo Sicuteri's review article in Headache, entitled ‘Dopamine, the second putative protagonist in headache’ (1). Sicuteri noted that ‘pain perception, vomiting, arterial blood pressure and affect, functions involved in migraine and other idiopathic headache, are partially controlled by dopaminergic systems, and therefore dopamine (DA) and 5-hydroxytryptamine (5-HT) may have a role in the pathogenesis of idiopathic headache’.

Sicuteri postulated the hypothesis that there is ‘a monoamine (5-HT and DA) postsynaptic receptor hypersensitivity in areas of the central nervous system involved in pain, vomiting, affect and arterial blood pressure’. He speculated that: (i) the spontaneous hypersensitivity might be caused by ‘chronic deficiency of agonists (5-HT, DA) at postsynaptic receptors’; (ii) ‘agonist deficiency in the synaptic cleft could be caused by impaired presynaptic function which regulates the concentration and release of mediator at the neuronal terminal’; or (iii) spontaneous hypersensitivity might be caused by ‘defective synthesis of mediator’.

Sicuteri concluded that ‘the connection between central nervous system physiology and idiopathic headache is obscure until one thinks of “central dysnociception” and idiopathic headache, when facts and imagination together provide an explanation for the disorder’. Since this thought-provoking paper, interest in the dopamine theory of migraine has waxed and waned and the dopaminergic hypothesis has received both support and criticism (2–6).

Throughout the past 30 years, basic and clinical research exploring migraine pathophysiology and potential new therapeutic targets has focused relatively little attention on dopamine, whereas the serotoninergic system has been exhaustively evaluated. More recently, considerable attention has been directed to the neuropeptides and inflammatory mediators (i.e. nitric oxide, calcitonin gene-related peptides).

Sicuteri suggested that ‘facts and imagination’ are necessary to provide an explanation for migraine's complex pathophysiology (1). Correspondingly, although the dopaminergic hypothesis of migraine has been overshadowed in basic science research, several researchers have revisited dopamine. Utilizing innovative and elegant animal models and advanced genetic screening techniques, these researchers search for novel clues to aid the ongoing pursuit of a more comprehensive understanding of migraines’ elusive pathogenesis.

(i) Dopamine genetics and migraine de Sousa SC, Karwautz A, Wober C, Wagner G, Breen G, Zesch HE et al. A dopamine D4 receptor exon 3 VNTR allele protecting against migraine without aura. Ann Neurol 2007; 61:574–8.

Objective: As dopamine plays an important role in the pathophysiology of migraine and antimigraine drugs have an effect on the dopamine system, the objective of this study was to examine the dopamine D4 receptor gene for involvement in the cause of migraine.

Methods: We tested a variable number of tandem repeats (VNTR) polymorphism in the dopamine D4 receptor gene, the exon 3 VNTR, in a sample of 190 family trios each with a proband with childhood migraine by using transmission disequilibrium test tests.

Results: We found a trend for transmission distortion of this marker in migraine, with the common seven- repeat allele of the VNTR transmitted 58 times and not transmitted 82 times [global likelihood ratio score (LRS) = 12.27, degrees of freedom (DF) = 6, P = 0.06; for the seven-repeat allele: χ² = 5.1, P = 0.02]. This effect came only from migraine without aura (MoA) (145 trios), with the common seven-repeat allele transmitted 45 times and not transmitted 69 times (global LRS = 15.18, DF = 6, P = 0.019: for the seven-repeat allele: χ² = 6.4, P = 0.01; odds ratio 0.47), whereas in migraine with aura (MA) (45 trios) there was no transmission distortion of the seven-repeat allele.

Interpretation: We conclude that seven-repeat allele of the dopamine D4 receptor VNTR is a protective factor for MoA. Because migraine is a common disorder, this protective effect may have contributed to the positive selection acting on the dopamine D4 receptor exon 3 VNTR seven-repeat allele in recent human history. We speculate that dopamine function in the lateral parabrachial nucleus is involved in MoA.

COMMENTARY

The last two decades have witnessed an explosion in migraine genetic research, leading to the discovery of three autosomal dominant genes responsible for familial hemiplegic migraine. For typical MA and MoA, there is significant genetic heritability; the pattern of heritability is likely to be complex, involving several susceptibility genes, and is most consistent with a polygenic-multifactorial model involving both genetic and environmental factors (7).

The search is on for the genes that increase susceptibility to, or protect against, the development of typical MA and MoA. The first putative dopaminergic migraine gene [a polymorphism in the gene that encodes the dopamine D2 receptor (DRD2) leading to increased susceptibility to MA] was identified by Peroutka and colleagues a decade ago (8). Subsequently, several other groups have been unable to identify relationships between polymorphisms in dopamine DRD1–DRD5 receptor genes and susceptibility to migraine (9–11).

Mochi and colleagues have examined several polymorphisms in dopaminergic genes and found a different distribution of alleles for a 48 base pair VNTR in the dopamine D4 receptor (DRD4) in MoA compared with controls and compared with MA; a seven-repeat allele was underrepresented in the MoA cases (12). Similar results were not observed in a smaller study (11). Subsequently, de Sousa and colleagues have recently investigated this same VNTR polymorphism in the DRD4 gene (‘the exon 3 VNTR’) in a sample of 190 family trios (case-parent), each with a proband with MoA or MA. MoA and MA were diagnosed by a paediatric neurologist via face-to-face interviews using International Classification of Headache Disorders (ICHD)-2 criteria (8). de Sousa and colleagues used a technique entitled transmission disequilibrium test (TDT). TDT is a family-based association test to evaluate for the presence of genetic linkage between a genetic marker and a trait. The authors confirmed Mochi's finding that the seven-repeat allele of the DRD4 receptor VNTR may be a protective factor for MoA (but not MA)—this conclusion was based on the fact that the allele was transmitted to affected children in lower-than-predicted numbers (8).

Interestingly, the DRD4 exon 3 VNTR has been associated with a number of human traits and disease, the most notable being attention-deficit hyperactivity disorder (ADHD)—presence of the VNTR increases susceptibility to ADHD. Unfortunately, like the majority of findings from susceptibility studies, how the DRD4 exon 3 VNTR is related to the underlying pathophysiology of migraine remains unknown.

McCallum LK, Fernandez F, Quinlan S, Macartney DP, Lea RA, Griffiths LR. Association study of a functional variant in intron 8 of the dopamine transporter gene and migraine susceptibility. Eur J Neurol 2007; 14:706–7.

Migraine is a common, genetically influenced neurovascular disorder. The dopamine transporter gene is a candidate for migraine association studies. This study tested a functionally linked variable number tandem repeat (VNTR) in intron 8 of the dopamine transporter gene (DAT^Int8) in 550 migraine cases (401 with aura, 149 without aura) and 550 non-migraine controls. χ² analysis of the DAT^Int8 revealed that the allele and genotype frequency distributions for migraine cases (including subtype analysis) and controls were not different (P > 0.1). These findings offer no evidence for an association of the DAT^Int8 with MA or MoA and therefore do not implicate the dopamine transporter gene as a modifier of migraine risk.

Fernandez F, Lea RA, Colson NJ, Bellis C, Quinlan S, Griffiths LR. Association between a 19 bp deletion polymorphism at the dopamine beta-hydroxylase (d.b.h.) locus and migraine with aura. J Neurol Sci 2006; 251:118–23.

Migraine is a debilitating neurological disorder, affecting 12% of White populations. It is well known that migraine has a strong genetic component, although the type and number of genes involved is unclear. Our previous work has investigated dopamine-related migraine candidate genes and has reported a significant allelic association with migraine of a microsatellite localized to the promoter region of the dopamine β-hydroxylase (d.b.h.) gene. The present study performed an association analysis in a larger population of case–controls (275 unrelated White migraineurs vs. 275 controls) examining two different genetic d.b.h. polymorphisms (a functional insertion/deletion promoter and a coding SNP A444G polymorphism). Although no significant association was found for the SNP polymorphism, the results showed a significant association between the insertion/deletion variant and disease (χ² = 8.92, P = 0.011), in particular in MA (χ² = 11.53, P = 0.003) compared with the control group. Furthermore, analysis of this polymorphism stratified by gender revealed that male individuals with the homozygote deletion genotype had three times the risk of developing migraine, compared with females. The d.b.h. insertion/deletion polymorphism is in linkage disequilibrium with the previously reported migraine-associated d.b.h. microsatellite and this insertion/deletion polymorphism is functional, which may explain a potential role in susceptibility to migraine.

COMMENTARY

In the search for migraine susceptibility or protective genes from the dopaminergic system, researchers have extended their search beyond dopamine receptor genes to include evaluation of dopamine transporter genes (12, 13) and genes coding for various proteins involved in dopamine synthesis and catabolism (14, 15).

The dopamine transporter protein (DAT) mediates the active reuptake of dopamine from the synapse and is a major regulator of dopaminergic neurotransmission. Correspondingly, variants in the DAT gene have recently been investigated as candidate genes affecting migraine susceptibility (12, 13). McCallum and colleagues found no evidence of an association between a VNTR in intron 8 of the DAT gene and MA or MoA in 550 migraine cases and 550 non-migraine controls (13). Cevoli and colleagues have sought to investigate the role of DAT in susceptibility to chronic migraine with medication overuse (16). They found that allele 10 of the DAT gene was significantly underrepresented in patients with chronic migraine associated with medication overuse when compared with episodic migraine sufferers; however, to complicate matters, there was no difference in the allelic distributions of the DAT gene between patients with chronic migraine with medication overuse and controls. Furthermore, the study did not have a chronic migraine without medication overuse arm. Consequently, interpretation of these findings is challenging.

Dopamine β-hydroxylase (d.b.h.) plays an important role in the noradrenergic system. d.b.h. catalyses the conversion of dopamine to norepinephrine. The level of individual d.b.h. activity has a strong genetic background. Fernandez and colleagues have performed an association analysis examining two different d.b.h. polymorphisms in 550 patients (275 controls and 275 with ICHD-2 typical MA or MoA) (17). The authors found that the homozygous deletion genotype of d.b.h. (DBH2) was associated with a 1.7-fold increased risk of developing migraine and twofold increased risk of developing MA; notably, the risk was increased 3.7-fold in men compared with 1.4-fold in women. The authors concluded that the DBH2 homozygous deletion genotype is a genetic risk factor for MA, particularly in men. Homozygous deletion of the DBH2 gene leads to increased dopamine and decreased norepinephrine due to deficient dopamine β-hydroxylase activity.

Interestingly, 30 years ago Gotoh and colleagues (14) reported that serum dopamine-β-hydroxylase activity levels were higher in migraineurs than in tension-type headache or control patients, although subsequent studies were contradictory (15). Recently, D'Andrea and colleagues have found that platelet levels of dopamine are increased in MoA (but not MA) and cluster headaches (18). Whether or not increased dopamine is due to altered d.b.h. is purely speculative.

Taken together, the genetic research evaluating the relationship between migraine and genes encoding dopamine receptors, dopamine transporter proteins and dopamine-β-hydroxylase has generated far more questions than answers. Thus far, no definitive conclusions regarding migraine susceptibility or protective genes from the dopaminergic system can be reached and further exploration with larger sample sizes is warranted.

(ii) Dopamine and migraine pathophysiology Bergerot A, Storer RJ, Goadsby PJ. Dopamine inhibits trigeminovascular transmission in the rat. Ann Neurol 2007; 61:251–62.

Objective: Clinical evidence, such as premonitory or postdromal symptoms, indicate involvement of dopamine in the pathophysiology of migraine.

Methods: To study the influence of dopamine on nociceptive trigeminovascular neurotransmission, we first determined using immunohistofluorescence that dopamine receptors were present in the rat trigeminocervical complex; then using extracellular recording techniques, we examined whether dopamine modulates cell firing in the trigeminocervical complex.

Results: We identified a discrete population of D1 receptors (median 11; interquartile range 7–30 neurons/hemisection) predominantly located in the deep laminae and a more abundant population of D2 receptors (median 75; interquartile range 30–99 neurons/hemisection) that were evenly distributed in the trigeminocervical complex. Intravenous dopamine had no effect on trigeminovascular neurons, whereas when dopamine was applied microiontophoretically, a potent reversible inhibition of l-glutamate-evoked firing was observed. The effect of microiontophoretically applied dopamine was dose dependent. Dopamine also strongly inhibited activation of trigeminocervical neurons in response to middle meningeal artery stimulation in vivo, with a maximum effect obtained within 10 min after the application and return to baseline within 30 min.

Interpretation: We conclude that central dopamine- containing neurons may play a role in modulating trigeminovascular nociception; these neurons offer an important target that will expand our understanding of migraine and may offer new directions for therapy.

COMMENTARY

Although clinical and pharmacological evidence supports the hypothesis that dopamine may be involved in migraine pathogenesis, no putative pathophysiological role has been established. Dr Bergerot and colleagues from Dr Goadsby's group therefore sought to characterize the distribution, size and density of dopamine receptors in the rodent trigeminocervical complex (TCC) and investigate the potential role of dopamine in trigeminovascular neurotransmission.

Using immunohistofluoresence, they examined for D1 and D2 dopamine receptors in the TCC. Both D1 and D2 receptors were identified in the TCC, with D1 receptor protein essentially present in the neuronal cell bodies and D2 receptor protein present in neuronal cell bodies and on proximal processes. Neurons expressing D1 receptors were found in relatively low density evenly distributed rostrocaudally and were most located in the deeper laminae. Although neurons expressing D2 receptors were also found homogeneously throughout the TCC, their density was higher and they were more likely to be in superficial laminae.

In order to determine the effect of dopamine on TCC neurons, electrophysiological recording was obtained from wide dynamic range neurons in the TCC responding to stimulation of the peri-middle meningeal artery (MMA) dura mater and with cutaneous receptive fields in the ophthalmic division of the trigeminal nerve. Control intravenous administration of saline had no significant effect on the activity evoked by stimulation of the MMA. Naratriptan rapidly and significantly decreased MMA-evoking firing, whereas intravenous administration of dopamine (which does not cross the blood–brain barrier) had no significant effect on the activity evoked by the dural stimulation. Similarly, spontaneous activity was not affected by intravenous dopamine.

To examine the effect of local microiontophoretic administration of dopamine, neurons identified as linked to stimulation of the peri-MMA dura mater and with receptive fields from V1 were tested for the stability of their baseline response to l-glutamate. Microiontophoretic administration of dopamine consistently, significantly and reversibly inhibited trigeminal firing in response to l-glutamate in a dose-dependent manner. The spontaneous activity of trigeminal neurons was also significantly altered by local dopamine administration. Furthermore, the firing rate evoked by MMA stimulation was also inhibited by local dopamine administration.

This study is certainly noteworthy, in that it establishes a previously unrecognized role for dopamine—an inhibitory modulator of nociceptive trigeminovascular input. The separation of D1 and D2 receptors into different subpopulations of neurons in the TCC suggests that these neurons may be subject to differential regulation by their dopaminergic input.

Based on the clinical observation that dopamine receptor antagonists are effective in the treatment of acute migraine, a logical prediction would have been that administration of dopamine would produce potentiation of trigeminovascular nociceptive transmission. Surprisingly, paradoxically, the opposite was observed—administration of dopamine led to inhibition of trigeminovascular nociceptive transmission. Bergerot and colleagues speculate that this unanticipated result may reflect differential effects of dopaminergic mechanisms at different stages of the migraine attack. They postulate that the data fit well with a role for dopaminergic modulatory dysfunction in the premonitory phase potentially contributing to premonitory symptoms such as neck pain.

This elegant study answers some questions and raises many others—it should serve to stimulate further interest in the dopaminergic hypothesis of migraine. Which other sites in the central nervous system utilize dopaminergic transmission to modulate trigeminovascular transmission is an important issue that Charbit and colleagues in Goadby's group have begun to address. The next abstract below begins to address this question; it was presented at the XIII Congress of the International Headache Society.

It is unclear how knowledge that dopamine can inhibit trigeminovascular transmission in a rat model will aid in our understanding of the mechanism of action of dopamine antagonists in aborting acute migraine attacks. Whether recognition that dopamine is involved in trigeminovascular nociceptive transmission will lead to novel drug candidates for the acute and/or prophylactic management of migraine remains purely speculative.

Charbit A, Goadsby PJ, Holland P. Stimulation or lesioning of dopaminergic A11 cell group affects neuronal firing in the trigeminal nucleus caudalis. Cephalalgia 2007; 27:605.

Introduction: The A11 nucleus, located in the posterior hypothalamus, provides the only known source of descending dopaminergic innervation for the spinal grey matter. The study aimed to investigate the effect of A11 stimulation and lesioning on trigeminovascular nociceptive transmission in the rat.

Methods: Male Sprague-Dawley rats were anaesthetized with propofol (20–25 mg kg⁻¹ h⁻¹). Extracellular recordings were made in the trigeminal nucleus caudalis (TNC), in response to electrical stimulation of the middle meningeal artery (MMA, 8–16 V, 0.2–1 ms, 0.5–0.8 Hz). Receptive fields were characterized by mechanical noxious and innocuous stimulation of the ipsilateral ophthalmic dermatome. After recording baseline firing evoked by MMA stimulation (20 sweeps) and receptive field nociceptive or innocuous stimulation (2 s), the A11 was either stimulated (5–50 µA, 0.5 ms, 5–100 Hz; n = 14) or lesioned (200–1000 µA, 0.5 ms, 20–50 Hz for 2–3 min; n = 8) and the effect on TNC firing determined.

Results: Stimulation of the A11 significantly inhibited MMA (F _4.4,48.5 = 2.59; P F _9.0,108.0 = 4.58; P n = 5) (MMA: F _1.3,3.8 = 1.65; P = 0.284; noxious pinch: F _1.3,2.6 = 2.12; P = 0.266). Lesioning of the A11 significantly facilitated evoked firing of neurons from the TNC (MMA: F _2.3,13.6 = 3.62; P F _3.0,14.9 = 4.60; P F _4.0,23.8 = 2.43).

Conclusion: Neurons in the A11 may through a dopaminergic mechanism modulate trigeminovascular nociceptive traffic.

(iii) Dopamine and migraine therapeutics Honkaniemi J, Liimatainen S, Rainesalo S, Sulavuori S. Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache 2006; 46:781–7.

Objective: To assess the efficacy and safety of i.v. haloperidol in treatment of acute migraine headache in a double-blind, randomized, placebo-controlled study design.

Background: Neuroleptics are mainly used as antiemetics in acute migraine. In a previous open trial haloperidol was effective in relieving migraine pain. DESIGN: Patients were randomized into two groups receiving intravenously either 5 mg haloperidol in 500 ml of normal saline or 500 ml of normal saline alone. Pain was assessed by visual analogue scale (VAS) before and 1–3 h after the infusion. If the patient felt no relief in pain intensity 1–3 h after the infusion and had received placebo, he/she then received haloperidol infusion as an open trial. The open trial also included seven patients who refused from the placebo-controlled trial. About 1 month after the infusion the patients were contacted by telephone and interviewed about the side-effects of the treatment.

Results: Forty patients were enrolled into the double-blind, placebo-controlled study. Before the infusion the VAS values were 7.7 in the haloperidol and 7.2 in the placebo group. After the infusion the VAS values were 2.2 in the haloperidol and 6.3 in the placebo group (P < 0.0001). Significant pain relief was achieved in 80% of the patients treated with haloperidol, whereas only three patients (15%) responded to placebo (P < 0.0001). Seventeen patients treated with placebo without response together with seven patients who refused from the placebo-controlled study participated in the open trial. In this group VAS declined from 6.7 to 2.4 and 79% of these patients felt significant pain relief. The most common side-effects caused by haloperidol were sedation and akathisia, the latter being more troublesome. These effects were very common in patients participating in the double-blind (80%) and open (88%) trials. Sixteen percent of the patients considered the side-effects intolerable and would not like the migraine attacks to be treated with haloperidol in the future. Three patients (7%) returned to the emergency ward because of a relapse.

Conclusions: This study shows that i.v. haloperidol is very effective in relieving migraine-associated pain. Because the majority of the patients had taken other medication without response, haloperidol appears to be an effective rescue medication even when other types of treatment have failed. Relapses are rare, but side-effects are common, limiting the use of haloperidol in some patients.

COMMENTARY

This clinical trial by Honkaniemi and colleagues adds haloperidol to the list of dopamine antagonists (along with prochlorperazine, chlorpromazine, metoclopramide, droperidol and domperidone) that have demonstrated significant efficacy in the treatment of migraine in a randomized, controlled, double-blind, placebo-controlled trial. In this study, haloperidol demonstrated very good efficacy in obtaining headache relief as assessed by a visual analogue scale (80% vs. 15%, P < 0.001). However, a similar percentage of haloperidol-treated patients in the double-blind arm (80%) also reported side-effects, mainly motor agitation (53%) and sedation (53%).

The atypical neuroleptics have the ability to bind to many types of receptors, including dopamine (D2 > D1), serontonin, histamine, and alpha-adrenergic receptors in the brain. The mechanism of action by which dopamine antagonists can alleviate both migraine-related nausea and vomiting and migraine-related pain remains unclear; however, it is probably related to action at D2 receptors and, to a lesser degree, due to antagonisms at 5HT2A receptors.

A recent paper by Siow and colleagues has comprehensively reviewed the literature on neuroleptics in headache (19). They have also reported on their open-label clinical experience at the Jefferson Headache Centre with (i) parenteral typical neuroleptics for acute migraine, status migrainous and refractory migraine; and (ii) the atypical neuroleptics quetiapine and olanzapine for the acute and prophylactic treatment of migraine.

Further basic science research is required to elucidate the mechanism of action by which dopamine antagonists can abort a migraine, status migrainous or refractory chronic migraine headache. Certainly, new safer and better-tolerated dopamine antagonists with efficacy in acute migraine would be welcomed. Whether or not there is a potential role for any of the current atypical neuroleptic medications in the acute and prophylactic management of migraine remains unclear, and further clinical research is necessary.

Headache is one of the top 10 reasons for going to the emergency department in the USA, with approximately six patients presenting to the emergency department every minute; the vast majority of these individuals have migraine. Currently, there is no consensus on standard of care and no routinely followed guidelines for the emergency department treatment of migraine. Recent studies have demonstrated that in US emergency departments, more than 35 different medications are utilized for the acute treatment of migraine; opioids are twice as commonly prescribed as more migraine-specific dopamine antagonist medications (20). Thus, many migraine patients leave the hospital still in pain or have headache recurrence (21, 22).

Emergency medicine physicians need to develop greater awareness of the effectiveness of dopamine antagonists in the management of both migraine-related nausea and pain. It is an obligation of physicians practising in the field of headache to assist their emergency department colleagues to develop an appreciation of the role of dopamine antagonists in the management of migraine.