Migraine/Headache

The pathogenesis of migraine, as well as cluster headache (CH), is yet a debated question. In this review, we discuss the possible role of tyrosine and tryptophan metabolism in the pathogenesis of primary headaches, including the abnormalities in the synthesis of neurotransmitters. High level of dopamine, low level of norepinephrine, and very elevated levels of octopamine and synephrine were found in the plasma of episodic migraine without aura. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward increased decarboxylase and reduced hydroxylase enzyme activities, favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity. In addition, we present biochemical studies performed in chronic migraine (CM) and chronic tension-type headache patients (CTTH) to verify if the same anomalies are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine-related metabolites are present only in CM patients while tryptamine plasma levels were found significantly lower in both CM and CTTH patients. Because of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold.

The pathogenesis of migraine chronification remains unclear. Functional and structural magnetic resonance imaging studies have shown impaired functional and structural alterations in the brains of patients with chronic migraine. The cerebellum and periaqueductal gray (PAG) play pivotal roles in the neural circuits of pain conduction and analgesia in migraine. However, few neurotransmitter metabolism studies of these migraine-associated regions have been performed. To explore the pathogenesis of migraine chronification, we measured gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels in the dentate nucleus (DN) and PAG of patients with episodic and chronic migraine and healthy subjects.

Migraine is a disabling primary headache disorder with socioeconomic burden. Medication overuse headache (MOH) is caused by chronic overuse of symptomatic drugs often observed in migraine patients. The approved for migraine prevention CGRP antagonists erenumab, fremanezumab, and galcanezumab are effective in migraine prophylaxis but there are only few data regarding efficacy on MOH.

Several functional neuroimaging studies on healthy controls and patients with migraine with aura have shown that the activation of functional networks during visual stimulation is not restricted to the striate system, but also includes several extrastriate networks.

Besides representing the place where a migraine attack generates, what is the physiological role of peptidergic control of arteriolar caliber within the trigemino-vascular system? Considering that the shared goal of most human CGRP-based neurosensory systems is the protection from an acute threat, especially if hypoxic, what is the end meaning of a migraine attack? In this paper, we have reviewed available evidence on the possible role of the trigemino-vascular system in maintaining cerebral perfusion pressure homeostasis, despite the large physiological fluctuations in intracranial pressure occurring in daily life activities. In this perspective, the migraine attack is presented as the response to a cerebral hypoxic threat consequent to a deranged intracranial pressure control aimed at generating a temporary withdrawal from the environment with limitation of physical activity, a condition required to promote the restoration of cerebral fluids dynamic balance.