The most important primary
headaches (i.e. independent disorders that are not caused by another disease) are
migraine,
tension-type headache and
cluster headache. All primary
headaches are in need of better treatments.
Migraine has a prevalence of 10% in the general population and its societal costs are high. Although the precise mechanisms underlying the pathophysiology of
migraine are still elusive, the last decades have witnessed some progress (e.g. involvement of
serotonin,
calcitonin gene-related peptide,
nitric oxide, etc).
Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing.
Glyceryl trinitrate (GTN), a
pro-drug for NO, causes
headache in normal volunteers and a so called delayed
headache that fulfils criteria for
migraine without aura in
migraine sufferers. Blockade of
nitric oxide synthases (NOS) by
L-NMMA effectively treats attacks of
migraine without aura. Similar results have been obtained for chronic
tension-type headache and
cluster headache. Inhibition of the breakdown of cGMP also provokes
migraine in sufferers, indicating that cGMP is the effector of NO-induced
migraine. Several relationships exist between NO,
calcitonin gene-related peptide and other molecules important in
migraine. Also
ion channels, particularly the K(
ATP) channels, are important for the action of NO. In conclusion, inhibition of NO production or blockade of steps in the NO-cGMP pathway or scavenging of NO may be targets for new drugs for treating
migraine and other
headaches. Indeed, selective n-NOS and i-NOS inhibitors are already in early clinical development.