Insights Into the Pharmacological Targeting of the Trigeminocervical Complex in the Context of Treatments of Migraine

Simon Akerman; Marcela Romero-Reyes


Expert Rev Neurother. 2013;13(9):1041-1059. 

In This Article

Nitric Oxide Synthase Inhibitors

NO donors and their ability to trigger migraine in patients is long established,[96,97] and so it is inevitable that nitric oxide synthase (NOS) inhibitors have been explored for the treatment of migraine. The mechanism of triggering migraine is still not clearly understood, with debate over vascular or central mechanisms. NO donors clearly cause vasodilation in both humans[97] and animal models,[99,184] but they also cause activation of neurons in the TCC that are not vascular related[185,186] as well as other areas of the brain related to migraine.[103] More interestingly however, NO donors trigger premonitory symptoms of migraine that are no different to spontaneous attacks,[187] occurring well after the vascular effects disappear. It is known that NO donors cause increase and release of CGRP at the TCC[188] and trigeminal ganglion.[189] Furthermore, levels of neuronal NOS are increased in the TCC.[189,190] Therefore, non-vascular mechanisms seem possible, if not likely, and therefore non-vascular NOS inhibitors may prove efficacious in the treatment of migraine. Certainly, preclinically non-specific NOS inhibition and a specific neuronal NOS inhibitor attenuate neurogenic dural vasodilation.[191] Interestingly, specific inducible and endothelial NOS inhibitors had no effect. Also non-specific NOS blockade inhibits Fos immunoreactivity in the TCC after dural[192] and capsaicin-evoked neuronal activation.[193] These data indicate that NO production in the TCC and potentially other areas of the brain may be involved in triggering migraine, and therefore blocking this may be therapeutic. A small study using a non-specific NOS inhibitor did abort migraine, indicating a proof-of-concept for this mechanism,[194] although the non-specific nature of the molecule used did increase blood pressure with effects on endothelial mechanisms. More recently, there has been focus on the non-vascular inducible NOS inhibition. GW274150, a highly selective inducible NOS inhibitor was unable to abort or prevent migraine in randomized, placebo-controlled studies, which has recently been reviewed in more detail by others.[195,196] This does leave neuronal NOS inhibition as the only unexplored avenue of therapy. Certainly, the indications of a neuronal mechanism are attractive, and the data indicate that neuronal NOS is activated by NO donors in the TCC. Neuronal NOS inhibitors may prove the next logical step in the emerging story of nitrergic mechanisms in migraine, and targets within the TCC and other areas of the brain, would seem to be a logical approach forward.