Calcitonin gene-related peptide (CGRP) and Nitric oxide (NO) (CGRP/NO)

The "CGRP / NO" designation refers to the synergistic signaling axis between Calcitonin Gene-Related Peptide (CGRP) and Nitric Oxide (NO), which plays a central role in the pathophysiology of migraine and other primary headaches. CGRP is a 37-amino acid neuropeptide primarily released from trigeminal sensory nerves, acting as a potent vasodilator and mediator of neurogenic inflammation (Durham, 2006). Nitric oxide is a gaseous signaling molecule that often acts downstream of CGRP or independently to induce vasodilation via the activation of soluble guanylyl cyclase (Olesen, 2008). Clinical evidence shows that NO donors can trigger migraine-like attacks and increase CGRP release, while CGRP receptor antagonists can block NO-induced vasodilation, highlighting a reciprocal relationship (Ashina et al., 2019). Because this entry combines two distinct molecular entities with different receptors and signaling mechanisms, it is considered a pathway or axis rather than a single therapeutic target. Therapeutic intervention in this pathway currently focuses heavily on CGRP-targeted therapies, including monoclonal antibodies and small-molecule antagonists (gepants), to alleviate migraine symptoms (Goadsby et al., 2017). Additionally, nitric oxide synthase (NOS) inhibitors have been investigated as potential treatments, though they have faced challenges in clinical development (Olesen, 2008). Understanding the interaction between these two molecules is vital for developing more effective combination therapies or multi-target drugs for refractory headache disorders.

Other names

CGRP-NO axisCGRP-NO pathwayCalcitonin gene-related peptide and nitric oxide signaling

Drugs targeting this axis work by either antagonizing the CGRP receptor, sequestering the CGRP ligand, or modulating the nitric oxide pathway (e.g., inhibiting nitric oxide synthase or phosphodiesterase) to prevent the pathological vasodilation and sensitization of the trigeminovascular system (Goadsby et al., 2017; Olesen, 2008).