The Serotonin and Migraine Story Continues

abstract & commentary

Source: Leone M, et al. The serotonergic agent m-chlrophenylpiperazine induces migraine attacks: A controlled study. Neurology 2000;55:136-139.

By now it seems clear that serotonin or 5-hydroxytryptophan (5-HT) is important in the pathophysiology of migraine. The exact mechanism, however, has not been fully elucidated. In an attempt to better understand at least the pertinent receptors involved, Leone and colleagues looked at the incidence of migraine in subjects given m-chlorophenylpiperazine (mCPP), a serotonin agonist with specificity at the 5-HT2B,2C,1A receptors. Thirty-nine patients (20 controls and 19 migraineurs with aura) were enrolled in a double-blind study to receive either 0.5 mg/kg of oral m-CPP or oral placebo.

Incidence of headache was reported for the following 24 hours. Serum levels were measured in both groups and found to be comparable. The total number of headaches after m-CPP (n = 18; 46.2%) did not differ from the total number after placebo (n = 12; 30.8%). There were, however, more IHS defined migraines after m-CPP (n = 16; 41% vs n = 5; 13%) (P < 0.02) than in the placebo group. Leone et al conclude that m-CPP can provoke more migraines than placebo and indicate that migraineurs are more likely to develop headache on m-CPP challenge than control subjects. The findings support the role of 5-HT2B,2C,1A receptors in the pathophysiology of migraine. Leone et al do not comment on why the overall incidence of headache was comparable in each group.


The relationship of serotonin and migraine has been well known. Over the years, several observations have been noteworthy: serum 5-HT levels increase during migraine; platelets release 5-HT during migraine; 5-HT metabolites appear in the urine of patients after a migraine headache; and serotonin infusions will provoke migraine. Furthermore, the recognition that 5-HT 1D/1B receptors are widely expressed on cerebral vasculature led to the development of the triptan class of migraine-abortive drugs. 5-HT is widely expressed within the brainstem and cortex, regions in which other important receptor types have been implicated. This study demonstrates a significant role for 5-HT2B,2C,1A receptor subtypes, which may open doors for better understanding of the central mechanism and point the way to future medication interventions. —jeffrey reich