Hypothesis: serotonin-1C receptor activation in migraine: an alternative point of view with therapeutic implication

Brewerton's observation that meta-chlorophenylpiperazine, the major metabolite of trazodone, with high affinity and intrinsic activity for the serotonin-1C receptor precipitates migraine headaches in subjects with a personal and/or family history of migraine, prompted Fozard and Gray to postulate that activation of serotonin-1C receptors plays a significant role in the initiation of the attack. Little note was taken, however, of the significant delay between administration of meta-chlorophenylpiperazine and the onset of the headaches. This delay prompts another hypothesis, that the vasoconstrictive action of this substance, as it wears off leads to rebound vasodilation, precipitating migraine. Under this hypothesis, specific serotonin-1C receptor activation is not a necessary condition for the genesis of the migraine attack. As a practical corollary, the vasoconstrictive effect of meta-chlorophenylpiperazine may have therapeutic potential.