NO Migraine

Migraine attacks are based on inflammation and nitric oxide production in the capillaries and nervous tissues of the brain. Drugs that impact NO have a major impact on migraine attacks.

What do angina/nitroglycerine, impotency/Viagra, and migraine/L-NMMA have in common? The answer is nitric oxide, NO, a potent vasodilator and messenger molecule derived enzymatically from the basic amino acid arginine. NO is ubiquitous, short-lived and associated with inflammation. One of the NO synthetases (iNOS) that make NO is inducible as part of the suite of inflammation genes under the control of NFkB. Other NOS enzymes are controlled by cellular calcium levels and since we will be talking about neurons, it is important to mention that neurons ultimately release neurotransmitters when an action potential reaches the synapse and causes a sharp increase in calcium.

NO acts on a cell by activating cellular GMP cyclase to produce cyclic GMP. cGMP in turn can activate MAP kinase or NFkB. Viagra, by the way, enhances the vasodilation effects of NO by inhibiting the breakdown of cGMP and thereby causing more dilation with a limited amount of NO. Nitroglycerine/glyceryl trinitrate (GTN) increase the amount of NO available to endothelial cells and relax coronary arteries.

People who suffer from migraines, migraineurs, are sensitive to NO donors such as GTN and have a migraine attack after a delay of 4-6 hours. The headaches are not usually preceded by the typical visual auras. Non-migraineurs have no response. These results suggest the critical role of NO in the early stages of the migraine attack. Inhibition of NOS by L-NMMA reduces symptoms in most migraineurs after a spontaneous attack starts. Metabolites of NO also increase during migraine attacks.

Viagra, which blocks breakdown of cGMP, also induces migraine attacks in migraineurs and it does not cause dilation of the middle cerebral artery, suggesting that vasodilation may be only associated with migraine attacks, but not integral. Histamine can also cause attacks, but requires the NO pathway.

NO appears to act by increasing the release of the neuropeptide called CGRP, because NO initiated attacks can be stopped by drugs that block the CGRP receptor.

Inflammation is both a precondition for migraine attacks and a response to administration of NO donors such as GTN. The inflammatory transcription factor NFkB is activated by GTN and elevated levels of inflammatory cytokines, IL-1, IL-6, are released. Pretreatment with parthenolide, the active ingredient in feverfew, which is used as a migraine prophylaxis, reduced activation of NFkB by GTN. This observation reinforces the view that migraine pain results from NO induced inflammation.

The most effective and selective treatment for migraine headaches are drugs that block the action of the 5-hydroxytryptamine (5-HT) receptors, e.g. triptans, such as pizotifen and methysergide. The 5-HT receptor stimulation can result in NO production and blocking these receptors, blocks subsequent NO production, inflammation and pain. Prophylactic administration of NOS inhibitors, such as L-NMMA or NO scavengers, such as hydroxocobalamin, can reduce attacks.

There is substantial evidence that anti-inflammatory lifestyle and diets have a significant impact on the frequency and intensity of migraine attacks, because they minimize the participation of inflammation and its product, NO.

Neeb L, Reuter U. 2007. Nitric oxide in migraine. CNS Neurol Disord Drug Targets. 6(4):258-64.