Pain-Sensitive Cranial Structures: Chemical Anatomy
The foundation of our current understanding of the anatomy of headache was laid over half a century ago by the work of Harold Wolff, Bronson Ray, and Wilder Penfield. They observed that mechanical stimulation of the brain parenchyma did not cause pain in awake patients who were undergoing craniotomies but that similar stimulation of the meninges and cerebral and meningeal blood vessels produced severe, penetrating, ipsilateral headache (Ray and Wolff, 1940; Penfield, 1935).
They identified intracranial painsensitive components, including portions of the meninges, such as the basal dura and the venous sinuses and their tributaries; neural structures, such as the glossopharyngeal, vagus, and trigeminal cranial nerves as well as the upper cervical spinal nerves; and vascular structures, such as dural arteries, the carotid, vertebral and basilar arteries, the circle of Willis, and proximal portions of cerebral, vertebral, and basilar branches. The finding that intracranial vascular structures are painsensitive was consistent with centuries-old observations that extracranial vessels become sensitized and distended during headache attacks.
These observations also formed one of the major underpinnings of the vasogenic theory of migraine: nociceptive axons have extensive branches, and one trigeminal ganglion cell may project to more than one large cerebral artery. In humans, the anatomy of the projections of trigeminal afferents to the dura mater has been well described (Moskowitz et al., 1987) but that to the major arteries of the circle of Willis has not. Anatomical dissection in primates suggests that trigeminal afferents from the first division join the carotid artery within its cavernous segment and subsequently project to the circle of Willis.
Two neurophysiological studies (Bove and Moskowitz, 1997; Strassman et al., 1996) indicate that the primary afferent fibers that innervate the dura mater are activated by mechanical, thermal, and chemical stimulation. These high-threshold polymodal nociceptors may become sensitized by exposure to solutions of low pH and exhibit properties similar to those of the small, unmyelinated fibers that innervate other tissues.
Trigeminovascular System: Primary Afferent Sensory Neurons
The important role that vascular and meningeal structures play in headache initiation is related to their rich innervation by the primary afferent neurons that originate within the trigeminal ganglia (primarily the first division) (Mayberg et al., 1984) and dorsal root ganglia of the upper cervical spinal nerves (Arbab et al., 1986).
Three types of nociceptive neurons that may be important in various types of head pain have been identified: small-caliber, unmyelinated, slow-conducting, pseudounipolar neurons called C fibers; small-diameter, lightly myelinated, more rapid-conducting fibers called A delta nociceptors; and a more recently discovered class of small-caliber fibers called “silent nociceptors” because they remain quiet during more normal nociceptive processes and fire only in response to high-intensity noxious stimulation (Handwerker et al., 1991; Schmidt et al., 1995). Stimulation of the small-caliber, unmyelinated C fibers results in the slow buildup of an aching, throbbing, or burning pain, while the faster-conducting A delta fibers probably transmit sharper initial pain sensations (Merrill, 2000).
Upon activation, primary afferent neurons transmit nociceptive information from perivascular terminals through the trigeminal (Mayberg et al., 1984) and first and second spinal (Arbab et al., 1986) ganglia to enter the brain stem at the level of the pons. The nociceptive fibers then descend to project centrally across synapses on to second-order neurons within ventrolateral (Burstein et al., 1998) regions of the trigeminal nucleus caudalis (TNC) (Lisney, 1983) and the dorsal horn of the upper cervical spinal cord.