FIGURE 3.

Proposed mechanism of activation of the trigeminovascular in migraine following cortical spreading depression (after Pietrobon & Moskowitz, 2014). During cortical spreading depression (CSD), neurons locally release various proinflammatory signalling molecules (a), which in turn induce glial synthesis of prostaglandins and cytokins (b) (direct pathway). These molecules activate the trigeminal receptors located on the pia and pial arteries, and produce a nervous signal running ortho and antidromically; orthodromically (c), this signal reaches the ganglion of the trigeminal nerve and transmits the nociceptive message to the central nervous system. The CSD‐induced antidromical activation of the trigeminal nerve (d) is supposed to follow the trigeminovascular pathway, especially along the middle meningeal artery and to release vasoactive proinflammatory peptides in the dura mater (indirect pathway). This produces vasodilatation, plasma extravasation and local activation of dural mast cells, the later producing a long‐lasting activation and sensitization of dural nociceptors