Unmasking the relationship between CGRP and glutamate: from peripheral excitation to central sensitization in migraine.

The exact mechanisms that trigger the activation of the trigeminovascular system in migraine remain unclear. The involvement of calcitonin gene-related peptide (CGRP) in migraine is well-documented, and treatments aimed at blocking CGRP activity have proven successful in reducing migraine attacks for some patients. However, around one third of individuals do not respond to these therapies, which are also limited by factors like cost, side effects, and contraindications. There is growing evidence suggesting that glutamate, an excitatory neurotransmitter, plays a crucial role in the onset and maintenance of migraine pain, partially by enhancing CGRP release. Increased glutamate levels have been linked to both peripheral and central sensitization, potentially contributing to the development and persistence of chronic migraine. The relationship between CGRP and glutamate is complex, with glutamate possibly acting as an upstream trigger for CGRP release. This review examines the interplay between CGRP and glutamate, and their involvement in both peripheral and central sensitization. It also explores the therapeutic potential of targeting either glutamate or CGRP, aiming to address both peripheral and central migraine mechanisms. Finally, the role of triggers in migraine initiation at the peripheral level is discussed, offering insights into potential preventive strategies.