The perception of migraine headache, which is mediated by nociceptive signals transmitted from the cranial dura mater to the brain, is uniquely exacerbated by exposure to light. Here we show that exacerbation of migraine headache by light is prevalent among blind persons who maintain non-image-forming photoregulation in the face of massive rod/cone degeneration. Using single-unit recording and neural tract-tracing in the rat, we identified dura-sensitive neurons in the posterior thalamus, whose activity was distinctly modulated by light, and whose axons projected extensively across layers I through V of somatosensory, visual and associative cortices. The cell bodies and dendrites of such dura/light-sensitive neurons were apposed by axons originating from retinal ganglion cells, predominantly from intrinsically-photosensitive retinal ganglion cells – the principle conduit of non-image-forming photoregulation. We propose that photoregulation of migraine headache is exerted by a non-image-forming retinal pathway that modulates the activity of dura-sensitive thalamocortical neurons.

Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater. Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation. Mast cell-induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression. Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal pain pathway believed to underlie intracranial headaches such as that of migraine.

Attacks of migraine with aura represent a phenomenon in which abnormal neuronal activity in the cortex produces sensory disturbances (aura) some 20 -40 min before the onset of headache. The purpose of this study was to determine whether cortical spreading depression (CSD)-an event believed to underlie visual aura-can give rise to activation of nociceptors that innervate the meninges-an event believed to set off migraine headache. CSD was induced in anesthetized male rats by stimulation of the visual cortex with electrical pulses, pin prick, or KCl; single-unit activity of meningeal nociceptors was monitored in vivo in the rat before and after CSD. Regardless of the method of cortical stimulation, induction of CSD was recorded in 64 trials. In 31 of those trials, CSD induced a twofold increase in meningeal nociceptor firing rate that persisted for 37.0 Ϯ 4.6 min in trials in which activity returned to baseline, or Ͼ68 min in trials in which activity remained heightened at the time recording was interrupted. In two-thirds of the trials, onset of long-lasting neuronal activation began ϳ14 min after the wave of CSD. The findings demonstrates for the first time that induction of CSD by focal stimulation of the rat visual cortex can lead to long-lasting activation of nociceptors that innervate the meninges. We suggest that migraine with aura is initiated by waves of CSD that lead up to delayed activation of the trigeminovascular pathway.

Objective-Cortical spreading depression (CSD) has long been implicated in migraine attacks that begin with visual aura. Having shown that a wave of CSD can trigger long-lasting activation of meningeal nociceptors -the first-order neurons of the trigeminovascular pathway thought to underlie migraine headache -we now report that CSD can activate central trigeminovascular neurons in the spinal trigeminal nucleus (C1-2).Methods-Stimulation of the cortex with pin prick or KCl granule was used to induce CSD. Neuronal activity was monitored in C1-2 using single-unit recording in anesthetized rats.Results-In 25 trigeminovascular neurons activated by CSD, mean firing rate (spikes/sec) increased from 3.6 ± 1.2 before CSD (baseline) to 6.1 ± 1.8 after CSD (p < 0.0001) for a period >13 min. Neuronal activity returned to baseline level after 30.0 ± 3.1 min in 14 units, and remained elevated for 66.0 ± 8.3 (22-108) min through the entire recording period in the other 11 units. Neuronal activation began within 0.9 ± 0.4 (0-2.5) min after CSD in 7 neurons located in laminae I-II, or after a latency of 25.1 ± 4.0 (7-75) min in 9 neurons located in laminae I-II, and 9 neurons located in laminae III-V. In 27 trigeminovascular neurons not activated by CSD, mean firing rate was 2.0 ± 0.7 at baseline and 1.8 ± 0.7 after CSD.Interpretation-We propose that CSD constitutes a nociceptive stimulus capable of activating peripheral and central trigeminovascular neurons that underlie the headache of migraine with aura.

Migraine sufferers frequently testify that their headache feels as if the calvarial bones are deformed, crushed, or broken (Jakubowski et al., 2006). This has lead us to postulate that nociceptive fibers supply the calvarial bones. We studied sensory innervation of the calvaria in coronal and horizontal sections of whole-head preparations of postnatal and adult mice, using immunostaining of peripherin – a marker of thinly-myelinated and unmyelinated fibers – and calcitonin gene-related peptide (CGRP) – a marker more typical of unmyelinated nerve fibers. In pups, we observed nerve bundles coursing between the galea aponeurotica and the periosteum; between the periosteum and the bone; between the bone and the meninges; as well as fibers that run inside the diploë in different orientations. Some dural fibers issued collateral branches to the pia at the frontal part of the brain. In the adult calvaria, the highest concentration of peripherin- and CGRP-labeled fibers were found in sutures where they appeared to emerge from the dura. Labeled fibers were also observed in emissary canals, bone marrow and periosteum. In contrast to pups, no labeled fibers were found in the diploë of the adult calvaria. Meningeal nerves that infiltrate the periosteum through the calvarial sutures may be positioned to mediate migraine headache triggered by pathophysiology of extracranial tissues, such as muscle tenderness and mild trauma to the skull. In view of the concentration of sensory fibers in the sutures, it may be useful to avoid drilling the sutures in patients undergoing craniotomies for a variety of neurosurgical procedures.