Chronic degeneration of dorsal raphe serotonergic neurons modulates cortical spreading depression: a possible pathophysiology of migraine.

The vascular serotonergic system in the brain has been implicated in the pathophysiology of migraine, however, involvement of the serotonergic nervous system of the brain parenchyma in the pathophysiology remains unclear. To investigate whether the brain parenchymal serotonergic nervous system is involved in the etiology of migraine, we prepared an experimental model of migraine by generation of cortical spreading depression (SD), characterized by spreading of neuronal/glial membrane depolarization accompanied by temporal elevation of the cerebral blood flow (CBF) throughout the cerebral cortical hemisphere in rats, which underwent pharmacological treatment for degeneration of serotonergic neurons in the dorsal raphe nucleus. We show here that (1) significant degeneration of serotonergic neurons in the dorsal raphe nucleus and serotonergic fibers in the cerebral cortex was observed in treated rats, (2) spreading velocity of the CBF changes was significantly increased in these rats, and (3) calculated width of the depolarization wave was significantly extended in these rats. These results indicate that the dorsal raphe serotonergic neurons modulate cortical spreading depression and might be involved in migraine pathology via a similar mechanism.