Dopamine Hypersensitivity in Migraine: Role in Apomorphine Syncope

Zompo, Maria Del; Lai, Ml; Loi, V.; Pisano, Maria Barbara

doi:10.1111/j.1526-4610.1995.hed3504222.x

Cited by 33 publications

(30 citation statements)

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“…The theory that hypersensitivity of the dopaminergic system may be involved in the pathogenesis of migraine has been supported by various authors on the basis of clinical, pharmacological and recent genetic evidence [66,67], and the D2 partial agonist, Aripiprazole, was found to offer relief from migraine headache [68]. Several studies reported that Aripiprazole might precipitate dyskinesia and other movement disorders [69][70][71].…”

Section: Aripiprazolementioning

confidence: 99%

A pathway profile-based method for drug repositioning

et al. 2012

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Finding new applications for existing pharmaceuticals, known as drug repositioning, is a validated strategy for resolving the problem of high expenditure but low productivity in drug discovery. Currently, the prevalent computational methods for drug repositioning are focused mainly on the similarity or relevance between known drugs based on their "features", including chemical structure, side effects, gene expression profile, and/or chemical-protein interactome. However, such drug-oriented methods may constrain the newly predicted functions to the pharmacological functional space of the existing drugs. Clinically, many drugs have been found to bind "off-target" (i.e. to receptors other than their primary targets), which can lead to undesirable effects. In this study, which integrates known drug target information, we propose a disease-oriented strategy for evaluating the relationship between drugs and disease based on their pathway profile. The basic hypothesis of this method is that drugs exerting a therapeutic effect may not only directly target the disease-related proteins but also modulate the pathways involved in the pathological process. Upon testing eight of the global best-selling drugs in 2010 (each with more than three targets), the FDA (Food and Drug Administration, USA)-approved therapeutic function of each was included in the top 10 predicted indications. On average, 60% of predicted results made using our method are proved by literature. This approach could be used to complement existing methods and may provide a new perspective in drug repositioning and side effect evaluation. Drug discovery is a time-consuming and laborious process. To bring a single de novo drug to the market, an average of more than $800 million is spent in a time period of ~15 years [1]. Moreover, about 90% of drugs fail during development in phase I clinical trials [2], a rate caused mainly by findings of low therapeutic efficacy and/or unacceptable toxicity [3,4]. Others are discovered to have similar drawbacks, even after approval by drug regulatory authorities (e.g. the US Federal Drug Administration (FDA)), or postmarketing. In exceptional circumstances, it is necessary to either modify the drug or even withdraw it from the market. The "thalidomide affair", a highly recognizable example of a drug having tragic unintended effects, is a typical example. Thalidomide was withdrawn from the market in the early 1960s because of teratogenic effects. However, it has since been reborn as an FDA-approved treatment for cancers and lepriasis owing to the discovery of new indications, namely immunomodulatory and anti-angiogenic activities [5][6][7][8].Despite enormous increases in novel technologies over recent times, the productivity of drug discovery efforts has actually decreased since the mid-1990s [9]. The need to define a novel strategy and/or utilize new resources in drug discovery is urgent. Drug repositioning, which aims to discover new indications for existing drugs, can shorten the development cycle and reduce the risk of u...

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Section: Aripiprazolementioning

confidence: 99%

A pathway profile-based method for drug repositioning

et al. 2012

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“…Dysosmia indicates an activation of the olfactory tubercle, which is particularly rich in dopaminergic fibers. The administration of apomorphine to a migraineur caused an episode of nausea, sweating, yawning, hypotension, vomiting and syncope at a dosage that is ineffective in non-migraineurs, further suggesting the existence of DA hypersensitivity [2]. Hypotension and occasionally syncope have been associated with migraine [10].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…However, the dopaminergic system also appears to play a major, still less recognized, role in migraine and dopamine (DA) can be considered the "second putative protagonist in headache" [1]. Several arguments suggest the involvement of DA in migraine pathophysiology [2,3].The dopaminergic system has a prominent role in motor and sensorial control, in modulating cognitive processes, and in the control of both prolactin and growth hormone secretion. Recently, a key role in the regulation of cerebral microcirculation has been demonstrated [4].…”

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Role of dopaminergic system in migraine

et al. 2001

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IntroductionDespite recent advances, the pathogenesis of migraine is still unclear. The study of migraine pathophysiology includes the investigation of neurotransmitters and their potential role in the development of the attack. Scientific and clinical interest has focused on the role of 5-hydroxytryptamine (5-HT). However, the dopaminergic system also appears to play a major, still less recognized, role in migraine and dopamine (DA) can be considered the "second putative protagonist in headache" [1]. Several arguments suggest the involvement of DA in migraine pathophysiology [2,3].The dopaminergic system has a prominent role in motor and sensorial control, in modulating cognitive processes, and in the control of both prolactin and growth hormone secretion. Recently, a key role in the regulation of cerebral microcirculation has been demonstrated [4]. Based on their structure and pharmacological characteristics, five subtypes of DA receptors have been described: D1, D4 and D5 are Gs protein-coupled receptors, D2 is a Gi protein-coupled receptor, and the signal transducing system of D3 is not yet completely characterized.Evidence for hypersensitivity of the dopaminergic system in migraineThe theory that hypersensitivity of the 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. Role of dopaminergic system in migraine Alessandra Cherchi Erminia Stochino Maria Paola Piccardi Maria Del ZompoAbstract 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.

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“…Other clinical aspects of migraine, such as gastrointestinal disorders, may also be ascribed to a dysfunction of the dopaminergic system. The administration of a very low dose of apomorphine, a selective D 1 and D2 dopaminergic agonist, to a migraineur caused an episode of nausea, sweating, yawning, hypotension, vomiting and syncope, which further suggests the existence of a hypersensitivity of the dopaminergic system in migraineurs [4]. Abstract Migraine is a common chronic disorder with an etiology still mostly unknown.…”

Section: Introductionmentioning

confidence: 99%

Dopamine genes and migraine

et al. 2000

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IntroductionThe study of the pathophysiological mechanisms of migraine includes the investigation of the neurotransmitter systems and their potential role in the development of the attack. Since the 1970s, many authors have studied the involvement of the dopaminergic system in the pathogenesis of the disease. Based on their structure and pharmacological characteristics, dopamine receptors have been classified into two main families: D1, including D1 and D5, and D2, including D2, D3 and D4. The dopaminergic system has a prominent role in motor and sensorial control, in the modulation of cognitive processes, and in the control of both prolactin and growth hormone secretion. Recently, a key role in the regulation of cerebral microcirculation has been demonstrated [1].The theory that hypersensitivity of the dopaminergic system is involved in the pathogenesis of migraine has been supported by various authors on the basis of clinical, pharmacological and recent genetic evidence. Clinical evidence of dopamine involvement was first described by Blau, who observed intense yawning, craving for some foods and altered sensorial perception during the initial phase of a migraine attack [2]. Yawning is a behavior controlled by numerous neurotransmitters and by neuropeptides which act at the level of the periventricular hypothalamic nucleus. Among the various neurotransmitters which elicit yawning, dopamine has proved to play a major role, acting through D2 postsynaptic receptors located in cell bodies of oxytocinergic neurons present in the periventricular hypothalamic nucleus, causing the release of oxytocin and subsequent yawning [3]. During attacks, nausea and/or vomiting, dysosmia and more yawning may occur. Nausea and vomiting are partly controlled by the activation of dopaminergic system through D 2 receptors located in the "chemoreceptor trigger zone" (CTZ) and in the nucleus of solitary tract in the brainstem. Dysosmia indicates an activation of the olfactory tubercle, which is particularly rich in dopaminergic fibers. Other clinical aspects of migraine, such as gastrointestinal disorders, may also be ascribed to a dysfunction of the dopaminergic system. The administration of a very low dose of apomorphine, a selective D 1 and D2 dopaminergic agonist, to a migraineur caused an episode of nausea, sweating, yawning, hypotension, vomiting and syncope, which further suggests the existence of a hypersensitivity of the dopaminergic system in migraineurs [4]. Abstract Migraine is a common chronic disorder with an etiology still mostly unknown. Several neurotransmitters such as dopamine and serotonin are considered to be involved in the pathogenesis of the disease and the study of their systems is crucial in the understanding of migraine. Dopaminergic receptors are variously represented in human CNS and periphery. The hypothesis that a hypersensitivity of the dopaminergic system may have a role in migraine is based on clinical and genetic data. Genetic data are represented by association studies using dopaminergic genes as can...

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Dopamine Hypersensitivity in Migraine: Role in Apomorphine Syncope

Cited by 33 publications

References 1 publication

A pathway profile-based method for drug repositioning

A pathway profile-based method for drug repositioning

Role of dopaminergic system in migraine

Dopamine genes and migraine

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