Pathogenesis of Migraine

Role of Neuromodulators

Giovanni D'Andrea, MD; Antonello D'Arrigo, PhD; Maurizio Dalle Carbonare, PhD; Alberta Leon, PhD


Headache. 2012;52(7):1155-1163. 

In This Article

Abstract and Introduction


The pathogenesis of migraine is still, today, a hotly debated issue. Recent biochemical studies report the occurrence in migraine of metabolic abnormalities in the synthesis of neurotransmitters and neuromodulators. These include a metabolic shift directing tyrosine metabolism toward the decarboxylation pathway, therein resulting in an unphysiological production of noradrenaline and dopamine along with increased synthesis of traces amines such as tyramine, octopamine, and synephrine. This biochemical alteration is possibly favored by impaired mitochondrial function and high levels of glutamate in the central nervous system (CNS) of migraine patients. The unbalanced levels of the neurotransmitters (dopamine and noradrenaline) and neuromodulators (eg, tyramine, octopamine, and synephrine) in the synaptic dopaminergic and noradrenergic clefts of the pain matrix pathways may activate, downstream, the trigeminal system that releases calcitonin gene-related peptide. This induces the formation of an inflammatory soup, the sensitization of first trigeminal neuron, and the migraine attack. In view of this, we propose that migraine attacks derive from a top-down dysfunctional process that initiates in the frontal lobe in a hyperexcitable and hypoenergetic brain, thereafter progressing downstream resulting in abnormally activated nuclei of the pain matrix.


Migraine is a disabling condition characterized by unilateral headache pain, pulsating in quality and lasting 4–70 hours, accompanied by photo-, phono-, osmo-phobia, nausea, and vomiting. Aura may precede the migraine attacks in about 30% of patients and, in some patients, occurs as an isolated symptom.[1] The etiology of migraine is still not completely understood. This is because of the multiple complex symptomatology characteristic of migraine (headache attacks and psychiatric, neurologic, and sympathetic symptoms) and difficulty in unifying these characteristics into one or more interelated pathophysiological processes.

A pathophysiological hypothesis that may reconcile with the proteiform symptomatology of migraine has been proposed by Welch. According to this hypothesis, migraine is a multifactorial (ie, biological and psychological) biobehavioral disorder[2] in which the crisis is a response to stressful agents within an hyperexcitable brain.[3] Genetic mutations and/or polymorphisms of genes, yet to be determined, that regulate neuronal mitochondrial energy, neurotransmitter metabolism, and ion channels in the central nervous system (CNS) are considered the main biological factors.[4] Menstrual cycle, pregnancy, lifestyle, diet, anxiety, chronic stress, etc, are among the main psychological factors.[5] Once the migraine threshold is primed, the frequency of the attacks depends on the type of stress and anomalies in the metabolism of neurotransmitters and neuromodulators that regulate the synapses of cortical, antinociceptive (antinociceptic system [ANS]), and sympathetic neurons.[6]

In the CNS, glutamic acid and aspartic acid are the main excitatory neurotransmitters, whereas gamma aminobutyric acid (GABA) is the inhibitory neurtransmitter.[7] The balance between these 2 systems constitutes the frame in which the other circuitries regulate the functions of the human brain. It has been hypothesized that anomalies in the metabolism of glutamate and GABA, together with those that govern pain and vegetative functions, such as serotonin (5-HT), dopamine (DA), and noradrenaline (NE), constitute the phenotypical biochemical causes of the migraine.[8]

Recent evidence also supports the old notion that elusive amines, such as tyramine (tyr) and octopamine (Oct), play a role in migraine pathogensis.[9] These amines, together with DA and NE, are products of two different metabolic pathways of tyrosine. Tyrosine hydroxylase generates 3,4-dihydroxyphenylalanine (DOPA), DA, and NE, with the last 2 compounds requiring the action of DOPA decarboxylase and dopamine β-hydroxylase (Dβ-H) enzymes, respectively. The alternative pathway, tyrosine decarboxylase, synthetizes tyr, Oct, and synephrine, with Oct and synephrine requiring in addition Dβ-H and phenylethanolamine-N-methyltransferase (PNMT) enzyme activities[10] (see the Figure). Although the hypothesis that tyr and Oct may contribute to pathogenesis of migraine was proposed several decades ago,[11] the recent discovery of a new class of G-protein-coupled receptors with high affinity for these amines in rodents and humans has fuelled ever-increasing scientific interest. The trace amine receptors (TAARs) are found in various tissues and organs, including specific brain areas such as the rhinencephalon, limbic system, amygdala, hypothalamus, extrapyramidal system, and locus coeruleus.[12] This and other evidence has led to the suggestion that tyr and/or Oct behave as neurotransmitters and neuromodulators via TAARs and other receptors (eg, catecholaminergic receptors), respectively, contributing to physiology of noradrenergic and dopaminergic synaptic transmission in the ANS.[13]

Figure 1.

Scheme of tyrosine metabolism in brain: tyrosine hydroxylase-, tyrosine decarboxylase- and monoamine oxidase (MAO)-related pathways. Bold arrows highlight possible biochemical alterations occurring in brain of migraine patients. As a consequence of impairment of dopamine β-hydroxylase (Dβ-H) enzyme activity, due to possible polymorphisms in the Dβ-H gene or its regulators, dopamine levels increase while that of noradrenaline decrease. On the other hand, a metabolic shift directing tyrosine metabolism toward the decarboxylation pathway, potentially due to a reduction in mitochondrial energy, results in abnormal high levels of trace amines such as octopamine and synephrine. Together, these alterations raise the possibility that abnormalities in both neurotransmitters (dopamine and noradrenaline) and neuromodulators (trace amines) and/or their interactions with their receptors play a role in the pathogenesis of migraine. See text for further explanation.

We hereby summarize briefly the results, mainly generated from our laboratory, that support a role for biochemical alterations of different neurotransmitters and neuromodulators in the pathophysiology of migraine. Based on this evidence, we propose that future research efforts aiming to comprehend the pathophysiological relevance of neuromodulators, such as trace amines, in the CNS, have the potential to provide for new, more effective, treatment options for migraine.


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