A role for
serotonin in
migraine has been supported by changes in circulating levels of
serotonin and its metabolites during the phases of a
migraine attack, along with the ability of
serotonin-releasing agents to induce
migraine-like symptoms. The development of
serotonin receptor agonists with efficacy in the clinic for the alleviation of
migraine pain further implicates
serotonin as a key molecule in
migraine. Several theories regarding the etiology of
migraine have been proposed. The vasodilatory theory of
migraine suggested that extracranial arterial dilation during an attack was related to
migraine pain; a theory supported when
vasoconstrictors such as
sumatriptan alleviated
migraine pain. The neurological theory of
migraine proposed that
migraine resulted from abnormal firing in brain neurons. Cortical spreading depression, one facet of the neurological theory, could explain the prodrome of
migraine. The neurogenic dural
inflammation theory of
migraine supposed that the dural membrane surrounding the brain became inflamed and hypersensitive due to release of
neuropeptides from primary sensory nerve terminals.
Substance P,
calcitonin gene related peptide and
nitric oxide are all though to play a role in the dural inflammatory cascade. Animal models of
migraine have been utilized to study the physiology of
migraine and develop new
pharmaceutical therapies. One model measures the shunting of blood to arteriovenous anastomoses based on a proposal that
migraine primarily involves cranial arteriovenous vasodilation. Another model utilizes electrical stimulation of the trigeminal ganglion to induce neurogenic dural
inflammation quantified by the resulting extravasation of
proteins. Pharmacological agents such as
meta-chlorophenylpiperazine (mCPP) and
nitroglycerin have also been used to induce dural extravasation in animals. Both compounds also induce
migraine attacks in individuals with a history of
migraine. In addition, Fos, a
protein produced by activation of the c-fos gene, has been measured as an index of
migraine-like
pain transmission to the CNS following chemical or electrical stimulation of the trigeminal nerve. A role for
serotonin in
migraine is further supported by the efficacy of
serotonin receptor ligands.
Sumatriptan is an agonist at 5-HT1D and
5-HT1B receptor subtypes, and effective in treating
migraine pain and associated symptoms. Recently, selective 5-HT1F agonists have been proposed for the treatment of
migraine, without the side effects associated with the present 5-HT1D and
5-HT1B receptor agonists. A role for 5-HT2B receptors has also been suggested the initiation of
migraine, supporting use of selective
5-HT2B receptor antagonists in
migraine. Thus, agents that modulate 5-HT1B, 5-HT1D, 5-HT1F and 5-HT2B receptors either have or may have clinical utility in the
therapy of
migraine headache.