The 5-hydroxytryptamine-nitric oxide connection: the key link in the initiation of migraine?

The evidence for an involvement of 5-hydroxytryptamine (5-HT) and nitric oxide (NO) in the initiation of migraine is reviewed. Based on this, the following scenario is proposed. Endogenous 5-HT, arising perhaps from platelets but more likely from perivascular 5-HT-containing neurons in response to different types of "stress", would activate 5-HT2B/5-HT2C receptors on endothelial cells of the cerebral vasculature to release NO. Nitric oxide would, by directly activating sensory neurons, induce neurotransmitter release, plasma extravasation, pain and hyperalgesia. The result would be induction of the "sterile" inflammatory response, believed to be the key step in the development of migraine.