Intracranial nociception.

Understanding intracranial nociceptive innervation is essential to understand the pathophysiology of headaches. Our knowledge about human intracranial nociception comes from sparse observations during neurosurgical procedures performed in awake patients, from human anatomical studies and from experimental studies in animals. In this article we review the anatomical and functional organization underlying nociceptive innervation. Intracranial nociception is mainly mediated by the trigeminal system, except in the posterior cranial fossa that is innervated by the first cervical roots. For decades, the dura mater, its vessels and major cerebral blood vessels were considered as the only intracranial pain-sensitive structures. Recent animal and human studies have suggested that smaller brain arteries and potentially pia mater might also be pain sensitive. Nociceptive neurons innervating intracranial blood vessels project via the ophthalmic division (V1) to the trigeminal ganglion and store several neurotransmitters including glutamate, substance P and calcitonin gene-related peptide (CGRP). The trigeminal ganglion, root and brainstem nuclei have a specific topographic and functional somatotopy. Progressive transition between the trigeminal spinal nucleus and the dorsal horn of the cervical spinal cord, and convergence of nociceptive inputs from the face, intracranial structures and the occipital area on the so-called "trigemino-cervical complex" may explain some headache features, relations between facial and occipital pain, and efficacy of occipital nerve stimulation in headache. The specific anatomic organization of the trigeminal system, from the primary-order neuron in the trigeminal ganglion, to the second-order neuron is the trigeminal nuclei, may explain a part of the various characteristics of headaches.