Dopamine and migraine: biology and clinical implications

In the last 30 years dopamine has been considered as playing a role in the pathogenesis of migraine. The literature indicates that migraineurs are hypersensitive to dopamine agonists with respect to some of the premonitory symptoms of migraine such as nausea and yawning. There are various non-specific dopamine D(2) receptor antagonists that show good clinical efficacy in migraine, and also a number of polymorphisms of dopaminergic genes related to migraine. Animal studies have also shown that dopamine receptors are present in the trigeminovascular system, the area believed to be involved in headache pain, and neuronal firing here is reduced by dopamine agonists. There appears to be little effect of dopamine on peripheral trigeminal afferents. We assess some of the limitations of the clinical studies with regard to the therapeutics, and those found in the studies that discovered differences in genetic polymorphisms in migraine, and consider the implications of this on a dopaminergic hypothesis of migraine.     

Dopamine receptor genes and migraine with and without aura: an association study

OBJECTIVE: To investigate the role of the dopamine receptor genes, DRD1, DRD3, and DRD5 in the pathogenesis of migraine. BACKGROUND: Migraine is a chronic debilitating disorder affecting approximately 12% of the white population. The disease shows strong familial aggregation and presumably has a genetic basis, but at present, the type and number of genes involved is unclear. The study of candidate genes can prove useful in the identification of genes involved in complex diseases such as migraine, especially if the contribution of the gene to phenotypic expression is minor. Genes coding for proteins involved in dopamine metabolism have been implicated in a number of neurologic conditions and may play a contributory role in migraine. Hence, genes that code for enzymes and receptors modulating dopaminergic activity are good candidates for investigation of the molecular genetic basis of migraine. METHODS: We tested 275 migraineurs and 275 age- and sex-matched individuals free of migraine. Genotypic results were determined by restriction endonuclease digestion of polymerase chain reaction products to detect DRD1 and DRD3 alleles and by Genescan analysis after polymerase chain reaction using fluorescently labelled oligonucleotide primers for the DRD5 marker. RESULTS: Results of chi-square statistical analyses indicated that the allele distribution for migraine cases compared to controls was not significantly different for any of the three tested gene markers (chi2 = 0.1, P =.74 for DRD1; chi2 = 1.8, P =.18 for DRD3; and chi2 = 20.3, P =.08 for DRD5). CONCLUSIONS: These findings offer no evidence for allelic association between the tested dopamine receptor gene polymorphisms and the more prevalent forms of migraine and, therefore, do not support a role for these genes in the pathogenesis of the disorder.     

Role of dopaminergic system in migraine

The theory that hypersensitivity of dopamine (DA) system is involved in the pathogenesis of migraine has been supported by various authors on the basis of clinical, pharmacological and, recently, genetic evidence. Apomorphine, a selective and specific DA agonist, has a cerebral vasodilatatory effect and increases blood flow significantly in the middle cerebral artery in migraineurs. Processes from central DA neurons terminate in close contact with penetrating arterioles and cerebral capillaries in the cerebral cortex. This finding reaffirms the role of central neurogenic mechanisms in the regulation of the cerebral circulation and, we believe, further supports the major role of dopamine in the neurogenic mechanisms of migraine. Various studies have been carried out to verify the involvement of DA in migraine pathogenesis using molecular genetics as a tool. A positive association between the “dopaminergic” phenotype of migraine without aura and the D2 receptor gene has been found. To explain dopaminergic hypersensitivity in migraine without aura, we will study the genes encoding proteins involved in the signal transduction system.     

The primary headaches: genetics,epigenetics and a behavioural genetic model

The primary headaches, migraine with (MA) and without aura (MO) and cluster headache, all carry a substantial genetic liability. Familial hemiplegic migraine (FHM), an autosomal dominant mendelian disorder classified as a subtype of MA, is due to mutations in genes encoding neural channel subunits. MA/MO are considered multifactorial genetic disorders, and FHM has been proposed as a model for migraine aetiology. However, a review of the genetic studies suggests that the FHM genes are not involved in the typical migraines and that FHM should be considered as a syndromic migraine rather than a subtype of MA. Adopting the concept of syndromic migraine could be useful in understanding migraine pathogenesis. We hypothesise that epigenetic mechanisms play an important role in headache pathogenesis. A behavioural model is proposed, whereby the primary headaches are construed as behaviours, not symptoms, evolutionarily conserved for their adaptive value and engendered out of a genetic repertoire by a network of pattern generators present in the brain and signalling homeostatic imbalance. This behavioural model could be incorporated into migraine genetic research.     

Dopamine and migraine: a review of pharmacological, biochemical, neurophysiological, and therapeutic data

The dopamine theory of migraine pathogenesis, first proposed by F. Sicuteri in 1977, has attracted renewed interest after an increased frequency of the dopamine D2 receptor (DRD2) gene allele Nco I C was found in patients with migraine with aura. Therefore we reviewed the relevant literature. The most compelling argument favoring an interictal hypersensitivity of dopamine receptors in migraineurs stems from pharmacologic studies of the gastric and autonomic effects of dopaminergic agents such as apomorphine, but none of these studies was blinded and placebo-controlled. Various DRD2 antagonists abort migraine attacks after parenteral administration, while there is circumstantial evidence that dopamine agonists may be useful for prophylaxis. Most drugs used in these trials, however, lack selectivity for dopamine receptors. Both in pharmacological and therapeutic studies most patients had migraine without aura. We conclude that data suggesting a primary role for the dopaminergic system in migraine pathogenesis are unconvincing. Based on well established interactions between central amines, a reduced release of serotonin between attacks could lower dopamine release which would lead to receptor hvpersensitivity.     

Piribedil Test in Migraine: Neruoendocrinological Aspects

SYNOPSIS
Piribedil is a direct central dopamine receptor agonist drug, clinically useful in the diagnosis of migraine. It mayalso be used in the study of migraine pathogenesis, through evaluating dopaminergic "tone".The observed effects of Piribedil on GH and PRL release, in this study, indicate the existence of dopaminereceptor hypersensitivity in migraine patients. Furthermore our data suggest also the involvement ofnoradrenergic systems in migraine pathogenesis. Estrogen levels do not influence these neuroendocrinologicalresponses to Piribedil, even though the Piribedil test in these female migraine patients was clinically positive (andtherefore diagnostically useful) only during the perimenstrual phase.     

Dopamine receptors--physiological understanding to therapeutic intervention potential

There are two families of dopamine (DA) receptors, called D1 and D2, respectively. The D1 family consists of D1- and D5-receptor subtypes and the D2 family consists of D2-, D3-, and D4-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a large superfamily of receptors with seven transmembrane domains, which are coupled to their intracellular signal transduction systems by G-proteins. The implications of DA receptors in neuropsychiatry and cardiovascular and renal diseases are discussed. Neuropsychiatry indications include Parkinson's disease, schizophrenia, migraine, drug dependence, mania and depression, and Gilles de la Tourette syndrome. The underlying dysfunction of dopaminergic systems and the potential benefits of dopaminergic therapy in these different indications are critically examined. With respect to the pharmacological treatment of Parkinson's disease, a range of DA agonists are in various stages of preclinical and clinical development. D2-receptor agonist activity is predominant in most effective antiparkinsonian DA agonists. However, in practice, it is difficult to treat patients for several years with DA agonists alone; therapeutic benefit is not sustained. Rather, the use of a combination of DA agonists and levodopa is considered preferable. Reports of the efficacy of DA partial agonists await confirmation, and recent clinical investigations also suggest the potential of D1 receptor agonists as antiparkinson drugs. Regarding migraine pathogenesis, clinical and pharmacological evidence suggests that DA is involved in this disorder. Most prodromal and accompanying symptoms may be related to dopaminergic activation. Several drugs acting on DA receptors are effective in migraine treatment. Furthermore, migraine patients show a higher incidence of dopaminergic symptoms following acute DA agonist administration, when compared with normal controls. In cardiology, the therapeutic benefits of DA agonists are noted in the treatment of heart failure. Low doses of DA are widely used for its specific dopaminergic effects on renal function, which are suggested to be beneficial, and for its alpha- and beta-adrenergic-mediated responses that occur with higher doses. However, studies have been unable to demonstrate that DA can prevent acute renal failure or reduce mortality. It appears that the significant progress that is being made in the molecular understanding of DA receptors will continue to have a tremendous impact in the pharmacological treatment of neuropsychiatric, cardiovascular, and renal diseases.     

Dopamine Hypersensitivity in Migraine: Role in Apomorphine Syncope

There is some evidence supporting a potential role of hypersensitivity of the dopaminergic system in the pathogenesis of migraine. In this case report, we describe a syncopal episode in a patient with migraine without aura after the administration of a very low dose of apomorphine, a classical agonist of dopaminergic receptors. The absence of cardiovascular risk factors in this patient suggests that the clinical event might have been caused by hypersensitivity of the dopaminergic system.     

Platelet dopamine: D2 receptor binding in patients with migraine

Clinical, genetic and pharmacological evidences suggest an abnormality of the dopaminergic system in the pathogenesis of migraine. Direct evidence of an abnormal metabolism of dopamine in migraine, however, is lacking. Platelets are a useful model to understand brain dopaminergic mechanisms. The present study has been undertaken to study the status of platelet dopamine receptor binding by carrying out radioligand receptor binding assay. Binding of ³H-spiperone to platelet membranes, known to label dopamine (DA)—D2 receptors, was conducted in 20 patients with migraine and an equal number of healthy controls. The equilibrium dissociation constant (Kd) in patients with migraine (1.71 ± 0.19 nM) was found to be significantly lower ( P  < 0.001) as compared with controls (3.14 ± 0.33 nM). However, no significant change was observed in the maximal number of binding sites (Bmax) in patients with migraine. No relationship of Kd with type of migraine, presence of vomiting, family history, frequency of attack, duration of illness and menstrual migraine was observed. The findings of the present study provide support for the involvement of the dopaminergic system in migraine.     

Relief from migraine headache with aripiprazole treatment

There have been many reports of the association between migraine headaches and psychiatric disorders as well as of the utility of dopamine antagonists in the treatment of migraine headache. There is increasing evidence to support the activation of dopaminergic systems as a primary component of migraine pathogenesis. This report documents 3 cases of female migraineurs who received the dopamine modulator aripiprazole for treatment of co-occurring psychiatric disorders and experienced a decrease in migraine frequency and severity. A hypothesis as to the mechanism of action of dopamine regulation in migraine treatment is discussed.     

Genetic risk factors in primary paediatric versus adult headache: complexities and problematics

Numerous candidate genes for migraine have been proposed on the basis of their possible functional role in its pathogenesis. Genetic polymorphisms have been evaluated in association studies, some of which have been suggested to be susceptibility markers for adult migraine. To date, however, none of the identified polymorphisms in adult migraine susceptibility have been investigated in children, raising the possibility that they may not be necessarily involved in paediatric migraine susceptibility. This paper reviews studies of the genetic basis of migraine and summarises our experience in genetic association studies in primary paediatric headache susceptibility.     

The role of the MTHFR gene in migraine

Migraine is a common neurological disorder and is characterized by debilitating head pain and an assortment of additional symptoms which can include nausea, emesis, photophobia, phonophobia, and occasionally, visual sensory disturbances. A number of genes have been implicated in the pathogenesis of this disease, including genes involved in regulating the vascular system. Of particular importance are the methylenetetrahydrofolate reductase (MTHFR) gene and the role it plays in migraine with aura. Migraine with aura has previously been shown to have a significant comorbidity with stroke, making the vascular class of genes a priority for migraine studies. In this report, we outline the importance of the MTHFR gene in migraine and also discuss the use of a genetic isolate to investigate MTHFR genetic variants. From this study, 3 MTHFR single nucleotide polymorphisms showing association with migraine in the Norfolk Island population have been identified, thus reinforcing the potential role of MTHFR in migraine susceptibility. Further studies will continue to build a gene profile of variants involved in the complex disease migraine and improve understanding of the underlying genetic causes of this disorder.     

Pathogenesis of the migraine attack

BACKGROUND: There is clinical experimental evidence that extracranial arterial vasodilation, extracranial neurogenic inflammation, and decreased inhibition of central pain transmission are involved in the pathogenesis of the migraine headache. The migraine aura is likely caused by a neurophysiologic phenomenon akin to Le?o's cortical spreading depression, a wave of short-lasting neuronal excitation that travels over the cerebral cortex, followed by prolonged depression of cortical neuronal activity. METHOD: A concept of the pathogenesis of the migraine attack is presented, in which the relation of the mechanism of the migraine aura and that of the migraine headache is considered parallel rather than sequential in nature. CONCLUSIONS: The process driving the pathogenesis of the migraine attack and susceptible to the migraine trigger factors may be located in the brain stem.     

Combined effects of ACE and MMP-3 polymorphisms on migraine development

Migraine is a primary headache disorder which involves both genetic and environmental components. Since angiotensin-converting enzyme (ACE) and matrix metalloproteinase (MMP) share the same homology, we investigated whether the MMP-3 and ACE I/D gene variants are involved in migraine risk and whether the ACE variant might act in combination with the MMP-3 genetic variant in patients with migraine. This is the first study to evaluate the association between MMP-3 and ACE polymorphisms, and migraine. Genotypes were determined by polymerase chain reaction. The frequencies of 5A5A genotypes of the MMP-3 and D allele of ACE were significantly elevated, but II genotypes of the ACE and 6A allele of MMP-3 significantly decreased in all patients. The combined DD/5A5A and ID/5A5A genotypes increased the risk of migraine. Individuals who were homozygous for the deletion (D) allele showed increased ACE activity. Subjects with the 5A5A genotype and/or D allele or with the combined DD/5A5A or ID/5A5A might be more susceptible to migraine development. In contrast, subjects with the II and/or 6A6A genotypes may be protected from migraine development. The greater activity of the 5A5A and DD genotypes might result in vascular reactivity that is more pronounced in migraine. Taken together, our data suggest that numerous genes may influence ACE activity. Discovery of new genes might better clarify the pathogenesis of migraine and open an avenue to therapeutic strategies against migraine.     

Dopamine and migraine: does Parkinson's disease modify migraine course?

As brainstem mechanisms and dopaminergic neurotransmission are involved in migraine pathophysiology, we decided to investigate the course of migraine in Parkinson's disease (PD), the paradigm of brainstem dopaminergic disease. We screened 237 consecutive PD out-patients by direct interview to assess the prevalence of lifetime and current migraine. Moreover, we compared the course of migraine in PD patients with that of otherwise healthy age- (+/- 3 years) and sex-paired migraine controls in a cross-sectional study. PD patients showed a lifetime migraine prevalence of 27.8% and a current migraine prevalence of 13.1%. A positive family history of migraine was less frequent in PD patients than in controls. The frequency of current migraine was significantly lower in PD patients than in controls (47.0% vs. 68.2%; odds ratio = 0.41, 95% confidence interval = 0.19-0.89). Approximately two-thirds of PD patients reported an improvement in or remission of migraine after PD onset. Effects of menopause on migraine course were similar in patients and controls. These findings suggest that PD might somehow shorten the clinical course of migraine. Possible explanations include a prolonged prophylactic effect by chronic dopaminergic therapy or a positive effect of PD pathophysiology, namely nigral degeneration, on migraine mechanisms.     

Update on the genetics of migraine

Genetics and Headache: The Role of the MTHFR Gene in Migraine Stuart S, Cox H, Lea R, Griffiths L. Migraine is a common neurological disorder and is characterized by debilitating head pain and an assortment of additional symptoms which can include nausea, emesis, photophobia, phonophobia, and occasionally, visual sensory disturbances. A number of genes have been implicated in the pathogenesis of this disease, including genes involved in regulating the vascular system. Of particular importance are the methylenetetrahydrofolate reductase gene (MTHFR) and the role it plays in migraine with aura. Migraine with aura has previously been shown to have a significant comorbidity with stroke, making the vascular class of genes a priority for migraine studies. In this report, we outline the importance of the MTHFR gene in migraine and also discuss the use of a genetic isolate to investigate MTHFR genetic variants. From this study, 3 MTHFR single nucleotide polymorphisms showing association with migraine in the Norfolk Island population have been identified, thus reinforcing the potential role of MTHFR in migraine susceptibility. Further studies will continue to build a gene profile of variants involved in the complex disease migraine and improve understanding of the underlying genetic causes of this disorder.     

Exclusion of 5-HT2A and 5-HT2C Receptor Genes as Candidate Genes for Migraine

Several lines of investigation suggest that the serotonergic system may be involved in the pathogenesis of migraine. In particular, drugs which block 5-HT₂ receptor subtypes appear to be effective migraine prophylactic agents. Therefore, chromosomal DNA regions overlapping the 5-HT_2A (13q14-q22) and 5-HT_2c (Xq22-25) receptor loci were analyzed for possible linkage to the clinical diagnosis of migraine. No evidence for linkage to either chromosomal region was found, although a small subset of migrainous families showed positive likelihood of odds (LOD) scores. However, a homogeneity (HOMOG) analysis provided no statistical evidence for locus heterogeneity. The coding region of the 5-HT_2A and 5-HT_2c receptor genes was also analyzed in migraine patients and unaffected controls using polmerase chain reaction and direct sequencing. No mutations were found in the deduced amino acid sequence of either receptor in the sample of migraineurs tested. These results indicate that DNA-based mutations in the 5-HT_2A and 5-HT_2c receptors are not generally involved in the pathogenesis of migraine.     

Trigemino-cervical reflex abnormalities in patients with migraine and cluster headache

BACKGROUND: Head pain arises within the trigeminal nociceptive system. Current theories propose that the trigeminal system is intimately involved in the pathogenesis of migraine. Short-latency responses can be recorded in sternocleidomastoid muscles after stimulation of the trigeminal nerve (trigemino-cervical reflex). This brainstem reflex could be a suitable method to evaluate the trigeminal system in migraine and CH. OBJECTIVE: The aim of the present study was to further elucidate the pathophysiology of migraine and cluster headache (CH) with special reference to the involvement of the central trigeminal system in the different forms of primary headache. METHODS: The trigemino-cervical reflex was investigated in 15 healthy subjects, in 15 patients having migraine with aura, in 15 patients with migraine without aura, and in 10 patients with CH. RESULTS: Significant abnormalities were observed in a great number of patients with both types of migraine and CH during the headache attacks, but only in migraine patients during the interictal period. The alterations are bilateral in migraine, unilateral in CH. CONCLUSIONS: Our results further support the relevance of brainstem mechanisms in the pathogenesis of migraine rather than of CH. These data, taken together with that from experimental head pain and functional imaging studies, demonstrate that primary headache syndromes may be distinguished on a functional basis by areas of activation specific to the clinical syndrome.     

Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders

Migraine is a complex, debilitating neurovascular disorder, typically characterized by recurring, incapacitating attacks of severe headache often accompanied by nausea and neurological disturbances. It has a strong genetic basis demonstrated by rare migraine disorders caused by mutations in single genes (monogenic), as well as familial clustering of common migraine which is associated with polymorphisms in many genes (polygenic). Hemiplegic migraine is a dominantly inherited, severe form of migraine with associated motor weakness. Family studies have found that mutations in three different ion channels genes, CACNA1A, ATP1A2, and SCN1A can be causal. Functional studies of these mutations has shown that they can result in defective regulation of glutamatergic neurotransmission and the excitatory/inhibitory balance in the brain, which lowers the threshold for cortical spreading depression, a wave of cortical depolarization thought to be involved in headache initiation mechanisms. Other putative genes for monogenic migraine include KCKN18, PRRT2, and CSNK1D, which can also be involved with other disorders. There are a number of primarily vascular disorders caused by mutations in single genes, which are often accompanied by migraine symptoms. Mutations in NOTCH3 causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebrovascular disease that leads to ischemic strokes and dementia, but in which migraine is often present, sometimes long before the onset of other symptoms. Mutations in the TREX1 and COL4A1 also cause vascular disorders, but often feature migraine. With respect to common polygenic migraine, genome‐wide association studies have now identified single nucleotide polymorphisms at 38 loci significantly associated with migraine risk. Functions assigned to the genes in proximity to these loci suggest that both neuronal and vascular pathways also contribute to the pathophysiology of common migraine. Further studies are required to fully understand these findings and translate them into treatment options for migraine patients.     

Platelet levels of dopamine are increased in migraine and cluster headache

OBJECTIVE: To measure plasma and platelet levels of dopamine in patients with migraine with aura, migraine without aura, and cluster headache. BACKGROUND: Clinical, genetic, and pharmacological evidences suggest that an abnormality of dopaminergic system plays a role in migraine pathogenesis. Direct evidence of an abnormal metabolism of dopamine in migraine, however, is lacking. METHODS: Plasma and platelet levels of dopamine were measured in patients with migraine with aura or migraine without aura during headache-free periods and in patients with cluster headache during the remission and active periods, as compared with healthy control subjects, using a multichannel electrochemical high-performance liquid chromatography system. RESULTS: Plasma levels of dopamine were not detectable with our methodology. Platelet levels of dopamine were higher in both types of migraine (migraine without aura = .20 +/- .17 ng/10(8) platelets; migraine with aura = .16 +/- .19 ng/10(8) platelets) than in control subjects (.10 +/- .11 ng/10(8) platelets), although in migraine with aura patients the difference was not significant. Patients with cluster headache showed the highest levels of platelet dopamine (.34 +/- .36 ng/10(8) platelets). CONCLUSIONS: Our results support the hypothesis that the dopaminergic system is impaired in migraine and cluster headache and suggest that high platelet levels of dopamine may represent an abnormal biochemical phenotypic trait of these primary headaches.