Fig. 2

Interaction Between Glutamate and CGRP Influenced by Peripheral Glutamate. (1) High levels of glutamate in the dura or blood vessels of the TG can more easily enter the brain due to the lack of BBB protection in these areas. (2) This glutamate binds to NMDA, AMPA, or kainate receptors at the peripheral side (only NMDA is shown in the figure), increasing Ca²⁺ influx and activating primary afferent neurons. (3) The signal is transmitted to second-order neurons in the TCC of the brainstem through glutamate released from the central end into the synaptic cleft. (4) The excitatory signal then propagates to higher brain regions involved in pain processing, such as the thalamus. (5) In addition to glutamate, CGRP is released from the central terminals of primary C fibers and activates its receptors on second-order neurons. (6) Activated second-order neurons release CGRP, which stimulates its receptors on nearby microglial cells. (7) Microglial cells, in response to CGRP receptor activation, release additional glutamate and inflammatory cytokines. This glutamate ensures the activation of second-order neurons and amplifies sensitization. TG: trigeminal ganglion, BBB: blood brain barrier, Ca²⁺: calcium, TCC: trigeminal cervical complex. CGRP: calcitonin gene-related peptide, NMDA: N-methyl-D-aspartic acid, AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, Created in https://BioRender.com