Figure 1.

Model of peripheral and central perivascular CGRP actions. In the periphery, CGRP (green ovals) released from dural trigeminal afferents acts on perivascular cells to cause vasodilation and neurogenic inflammation, with positive feedback loops (blue arrows) leading to peripheral sensitization.³³ Nociceptive signals are relayed to the CNS to the thalamus directly and via the parabrachial nucleus. In the CNS, release of CGRP (green ovals) from parabrachial neurons into the posterior thalamic region modulates neural signaling. CGRP in the brain also causes vasodilation,⁴⁹ which could lead to neural activation by vascular-neural coupling⁵¹ and further dilation of vessels in a positive feedback loop (blue arrows) that triggers further CGRP release. CGRP-mediated neuromodulation of glutamatergic synapses results in central sensitization³³ and signaling to the cortex that leads to migraine symptoms of photophobia and pain.