Pathogenesis of Migraine: Role of Neuromodulators

Abstract

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.

Negative life events and migraine: a cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline data

“…Wittstein et al [36] reported a series of cases of cardiac dysfunction precipitated by acute emotional stress, known as the “broken heart” syndrome. Those authors suggested that this syndrome could be related to acute sympathetic stimuli, a neuromodulation pathway also potentially involved in migraine pathophysiology [37]. Similarly, the activation of the hypothalamus-pituitary-adrenal axis in stressful situations [38,39] may also be associated with a higher migraine activity [40].…”

Dopaminergic symptoms in migraine

“…In their study, D'Andrea et al also suggest that during the migraine attack, impaired energy metabolism shifts tyrosine metabolism from hydroxylation, which physiologically gives rise to a metabolic cascade leading to catecholamine synthesis, toward decarboxylation, resulting in increased synthesis of trace amines (tyrosine, octopamine, synephrine). The imbalance between neurotransmitters (DA, norepinephrine) and neuromodulators (trace amines) activates the trigeminovascular system [13]. Receptor binding studies show that peripheral blood lymphocytes from migraineurs contain higher DRD3, DRD4 and DRD5 densities than control lymphocytes, with no differences in radioligand affinity.…”

Is migraine a risk factor for the occurrence of eating disorders? Prevalence and biochemical evidences

“…This, together with the premonitory symptoms that precede the migraine attacks (nausea, depression, thirst, sexual excitement, anger, hyperosmia, etc.) suggest that a hypothalamic and limbic disfunction(s) play a role in pathogenesis of migraine [25][26][27].…”