SYNOPSIS Stimulation of the locus ceruleus produces vasoconstriction in the intracerebral circulation and vasodilatation in the extracerebral circulation. The latter is mediated by the seventh cranial nerve, involving a non‐cholinergic transmitter. These vascular changes are reminiscent of those occurring in migraine. Stimulation of the trigeminal ganglion or of the trigeminal divisions produces a reflex dilatation in the external carotid territory also mediated by non‐cholinergic fibers in the seventh nerve. It is postulated that, in migraine, activation of the locus ceruleus would produce vasoconstriction in the cerebral circulation and dilatation extracerebrally. Such an effect would account for both the neurological symptoms of migraine and the observed changes in blood flow and vascular reactivity. Dilatation in the external carotid territory could lead to further reflex changes by activation of the central pathways described. Changes in locus ceruleus activity could be responsible for the pain of the headache phase of migraine, by disrupting a descending pain control system.

Stimulation of the trigeminal nerve or ganglion in the cat caused a frequency-dependent reduction in carotid vascular resistance. Systemic arterial blood pressure (SABP) decreased at low frequencies (0.2 to 5 sec-1) and increased at higher frequencies, thus increasing carotid blood flow at the higher frequencies. The effect on resistance was predominantly ipsilateral and was unaltered by cervical sympathectomy, but was abolished or substantially reduced by section of the trigeminal root proximal to the ganglion. Diminution of carotid vascular resistance was replicated by stimulation of the greater superficial petrosal (GSP) nerve without any change in SABP. Section of the seventh cranial nerve reduced or abolished the response to stimulation of the trigeminal nerve but not that from the GSP nerve. The trigeminal response was prevented by ganglion-blocking drugs in seven out of eight cats. The resistance response was unaffected by noradrenergic, cholinergic, serotonergic, and histamine-2 blocking agents. No neural connection could be demonstrated between the GSP and the trigeminal ganglion, and the vascular response to GSP stimulation persisted after trigeminal section. It is concluded that activation of the trigeminal system increases carotid blood flow by a pathway involving the seventh cranial nerve, the GSP and Vidian nerves, and a parasympathetic synapse employing an unconventional transmitter. A varying proportion of the response (greatest in the third division) may be mediated by antidromic activation of trigeminal nerves. These findings may have clinical implications for the vascular changes of migraine and other facial pain.

We tested the idea that migraine triggers cause cortical activation, which disinhibits craniovascular sensation through the nucleus raphe magnus (NRM) and thus produces the headache of migraine. Stimulation of the dura mater and facial skin activated neurons in the NRM and the trigeminal nucleus. Stimulation of the NRM caused suppression of responses of trigeminal neurons to electrical and mechanical stimulation of the dura mater, but not of the skin. This suppression was antagonized by the iontophoretic application of the 5-HT(1B/1D) receptor antagonist GR127935 to trigeminal neurons. Migraine trigger factors were simulated by cortical spreading depression (CSD) and light flash. Activity of neurons in the NRM was inhibited by these stimuli. Multiple waves of CSD antagonized the inhibitory effect of NRM stimulation on responses of trigeminal neurons to dural mechanical stimulation but not to skin mechanical stimulation. The cortico-NRM-trigeminal neuraxis might provide a target for a more universally effective migraine prophylactic treatment.