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.