Figure 2.

Induction of migraine attack due to sensitization of trigeminal ganglia and disturbed glutamatergic release. TRPA1 receptors in sensory neurons in trigeminal ganglia (TG) activate under environmental irritants taken by inhalation, ingestion or in an unknown mechanism. Activation of the TRPA1 receptor stimulates the release of calcitonin gene-related peptide (CGRP) that may enter bloodstream during migraine attack. CGRP receptor is expressed by majority on the neurons forming myelinated TG A-fibers, as well as on smooth muscles of dura’s vasculature. CGRP receptor stimulation increases blood flow. Besides CGRP, activated TG neurons secrete nitric oxide (NO). These mediators stimulate further the surrounding glial cells to produce interleukin-1β (IL-1β) that in turn leads to increased activity of cyclooxygenase (COX), associated with production of proinflammatory prostaglandin E2 (PGE2). This phenomenon may be one of foundations of the TG neurons sensitization. Subsequently, CGRP released by TG neurons may also promote release of tumor necrosis factor-α (TNF-α) in the glial satellite cells. That may cause a positive feedback loop of further TG-neuronal synthesis and secretion of CGRP. Furthermore, the released TNF-α may itself sensitize TG neurons and inflict overproduction of various other proinflammatory cytokines. Activation of TRPA channels increase the intracellular calcium ion levels (Ca²⁺), similarly to L-type of Voltage Gated Calcium Channel (CaV2.1). Mutations in CACNA1A gene lead to enhanced Ca²⁺ currents. The enhanced Ca²⁺ influx lead to excitation-inhibition imbalance and enhanced glutamate release. The interaction between glutamate and pre- and postsynaptic glutamate NMDA receptors (NMDAr) may facilitate the cortical spreading depression (CSD)—believed as one of the causes of migraine attack. Ca²⁺ channel blockers affect the CaV2.1 channels and reduce excessive Ca²⁺ influx to the cells, normalizing glutamate release and thus may be also used in the treatment of migraine headaches.