Extracranial projections of meningeal afferents and their impact on meningeal nociception and headache

Pain. 2013 Sep;154(9):1622-1631. doi: 10.1016/j.pain.2013.04.040. Epub 2013 Apr 27.


Headaches can be evoked by activation of meningeal nociceptors, but an involvement of pericranial tissues is debated. We aimed to examine a possible extracranial innervation by meningeal afferents in the rat. For in vivo neuronal tracing, dextran amines were applied to the periosteum underlying the temporal muscle. Labeling was observed 2 days later in the parietal dura mater, trigeminal ganglion, and spinal trigeminal nucleus with confocal and electron microscopy. In the hemisected rat head, extracellular recordings were made from meningeal nerve fibers. Release of calcitonin gene-related peptide (CGRP) from the cranial dura mater during noxious stimulation of pericranial muscles was quantified. In vivo capsaicin was injected into the temporal muscle while meningeal blood flow was recorded. In the parietal dura mater, labeled C- and Aδ fibers ramified extensively, accompanied the middle meningeal artery, and passed through the spinosus nerve into the maxillary and mandibular, but not the ophthalmic division of the trigeminal ganglion. Some fibers could be traced into the ipsilateral spinal trigeminal nucleus. Electrophysiological recordings revealed afferent fibers with mechanosensitive receptive fields both in the dura mater and in the parietal periosteum. Noxious stimulation of the temporal muscle caused CGRP release from the dura mater and elevated meningeal blood flow. Collaterals of meningeal nerve fibers project through the skull, forming functional connections between extra- and intracranial tissues. This finding offers a new explanation of how noxious stimulation of pericranial tissues can directly influence meningeal nociception associated with headache generation and why manual therapies of pericranial muscles may be useful in headaches.

Keywords: Afferent recording; Blood flow; Headache; Meningeal nociception; Neuronal tracing; Neuropeptide release.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Capsaicin / pharmacology
  • Dextrans / metabolism
  • Disease Models, Animal
  • Dura Mater / pathology
  • Dura Mater / ultrastructure
  • Electric Stimulation / adverse effects
  • Headache / pathology*
  • Male
  • Meninges / blood supply
  • Meninges / pathology*
  • Meninges / ultrastructure
  • Nerve Fibers / pathology
  • Neural Conduction / drug effects
  • Neurons, Afferent / physiology*
  • Nociception / physiology*
  • Rats
  • Rats, Wistar
  • Trigeminal Ganglion / pathology
  • Trigeminal Ganglion / ultrastructure
  • Trigeminal Nuclei / pathology
  • Trigeminal Nuclei / ultrastructure


  • Dextrans
  • Calcitonin Gene-Related Peptide
  • Capsaicin