Nitric oxide: emerging implications for headache mechanics

The involvement of nitric oxide (NO) in the pathophysiology of primary headaches was suggested by several authors during the last decade. Migraine, cluster headache, tension headache, and cervicogenic headache have been extensively studied on the basis of NO donor headache pain. Different mechanisms seem to be involved in the generation of pain in these clearly different clinical head pain disorders. NO could control all the mechanisms leading to head pain. In migraine NO is correlated with endothelial activation, in cluster headache with a brainstem unravelling of the on/off regulatory clocks, in cervicogenic headache with a cytokine-dependent pain, and in tension-type headache with a sensitization of pain pathways at the spinal/trigeminal level. The next natural frontier in the study of pain in primary headaches seems to be the functional study of the relationship between NO and the immune regulatory system.