The sensory innervation of the calvarial periosteum is nociceptive and contributes to headache-like behavior

Abstract

Headaches are thought to result from the activation and sensitization of nociceptors that innervate deep cephalic tissues. A large body of evidence supports the view that some types of headaches originate intracranially, from activation of sensory neurons that innervate the cranial meninges. However the notion of an extracranial origin of headaches continues to be entertained, although the identity of deep extracranial cephalic tissues which might contribute to headaches remains elusive. Here we employed anatomical, electrophysiological, and behavioral approaches in rats to test the hypothesis that the sensory innervation of the calvarial periosteum is nociceptive. Neural tracing indicated that the calvarial periosteum overlying the frontal and parietal bones is innervated primarily by small and medium-sized neurons in the trigeminal ganglion’s ophthalmic division. In vivo single unit recording in the trigeminal ganglion revealed that calvarial periosteal afferents have slowly conducting axons, are mechanosensitive and respond to inflammatory mediators, consistent with a nociceptive function. Two distinct neuronal populations were distinguished based on their peripheral axonal trajectory: one that reached the periosteum through extracranial branches of the trigeminal nerve, and another that took an intracranial trajectory, innervating the cranial dura and apparently reaching the periosteum via the calvarial sutures. In behavioral studies, inflammatory stimulation of these afferents promoted periorbital tactile hypersensitivity, a sensory change linked to primary headaches. Activation and sensitization of calvarial periosteal afferents could play a role in mediating primary headaches of extracranial and perhaps also intracranial origin, as well as secondary headaches such as post-craniotomy and post-traumatic headaches. Targeting calvarial periosteal afferents may be effective in ameliorating these headaches.

Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: Implications for extracranial origin of headache

“…Because the up-regulated genes were linked to activation of mast cells, T cells and natural killer cells 43, 44 , production of cytokines, cell adhesion, cell-cell signaling, glycoprotein production 45 and disruption of proper NF-kB function 46, 47 , whereas the down-regulated genes were linked to repression of TNF-alpha, IL-6, and macrophage activation 48, 49 , and to prevention of cell lysis through inhibition of NK, T, and B cells 50 , we interpret these findings as suggesting that the molecular environment in which periosteal pain fibers exist is inflamed and that this localized inflammation can activate, or lower the activation threshold of trigeminal nociceptors that reach the affected periosteum through suture branches of intracranial meningeal nociceptors 51 and somatic branches of the occipital nerve 52 . Accordingly, we conclude that the localized extracranial pathophysiology we identified (i.e., periosteal inflammation) in the CM patients should be considered as evidence that some migraine attacks can originate outside the head.…”

Modulation of intracranial meningeal nociceptor activity by cortical spreading depression: a reassessment

“…The exposed dura was bathed with a modified synthetic interstitial fluid (SIF) consisting of (in mM) 135 NaCl, 5 KCl, 1 MgCl 2 , 5 CaCl 2 , 10 glucose, and 10 HEPES at pH 7.2. Single-unit activity of meningeal nociceptors (1 U/rat) was recorded in the ipsilateral (left) trigeminal ganglion using a contralateral approach, as described recently (Zhao and Levy 2014) and see also Fig. 1.…”

“…First, we recorded the activity of meningeal nociceptors in the trigeminal ganglion using an electrode that was inserted into the ganglion through the contralateral cortex (Zhao and Levy 2014), thus preventing a resultant CSD in the ipsilateral cortex. We further minimized the possibility of direct stimulation of meningeal nociceptors with RF over the transverse sinus by inducing CSD experimentally in the frontal cortex, a caudal cortical region covered by dural tissue that is innervated by only a small percentage of neurons that also have RF on the transverse sinus.…”

Post-Traumatic Headache Therapy in the Athlete

“…Some have suggested that activation and sensitization of calvarial periosteal afferents could play a role in mediating secondary headaches such as post-craniotomy and PTH [75]. It is proposed that inflammatory evoked enhancement of peripheral cranial nociception, rather than changes in supraspinal pain mechanisms contribute to the initial development of PTH [76].…”