Peptide neurotransmitters (calcitonin gene-related peptides especially) are very powerful vasodilators. They are released through the stimulation of the trigeminal nerve that is distributed into the intracranial arteries. Perivascular edema occurs (this is caused by the increase in the concentration of plasma as plasma proteins in the perivascular space). This in turn leads to mechanical stretching which then leads to activation of the pain nerve endings found in the dura. This is then called a migraine.

Drugs that is used in the treatment of migraines include: ergot alkaloids, NSAID’s, β-adrenoceptor blockers, Calcium channel blockers, tricyclic antidepressants and SSRI’s as well as antiseizure agents.

The mechanism of action of these drugs helps in the treatment of migraines in two ways. Firstly, by preventing vasodilation through the activation of direct 5-HT agonists that causes vasoconstriction. This leads to the inhibition of the stretching of the pain endings in the dura.
Secondly by inhibiting the release of vasodilation peptides. This is done by the activation of 5-HT_1D/1B receptors found on the nerve endings on presynaptic trigeminal. This causes a decrease in excessive firing of these nerve endings.