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Pain-Sensitive Cranial Structures: Chemical Anatomy

Wednesday, Apr 15 2009


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.

Pain Transmission Within the Central Nervous System
A large number of C-fiber afferent fibers contain substance P (Messlinger et al., 1993), calcitonin gene - related peptide (Nozaki et al., 1990), and neurokinin A, as well as other neurotransmitters and neuromodulators, in their central and peripheral (e.g., meningeal) axons. These neuropeptide-containing neurons express a tyrosine kinase receptor (Merrill, 2000). C fibers that do not contain neuropeptides express a surface lectin epitope that can be stained with IB4 (Bennett et al., 1996).

Neuropeptide-containing trigeminovascular afferents terminate within the superficial lamina (I and II) of the TNC (Schaible et al., 1997), where many of them synapse on projection neurons to other brain stem sites or the thalamus. C fibers that do not contain neuropeptides terminate within inner portions of lamina II and are thought to be heat nociceptors (Merrill, 2000).

Glutamate is the primary neurotransmitter in C fibers and is co-stored with substance P, neurokinin A, and calcitonin gene - related peptide. Activation of the peripheral nociceptor results in the generation of a depolarizing current that moves along the C fiber to cause the central release of glutamate and neuropeptides into the synaptic cleft. Glutamate in turn binds as an agonist to both prejunctional and postjunctional glutamate receptors (Bausbaum, 1999).

Glutamate receptors fall into two categories: ionotropic receptors, which are directly linked to calcium and sodium ion channels, and metabotropic receptors, which exert their effect via G-protein linkage to protein kinase second messengers. The ionotropic receptors include the N-methyl-Daspartate (NMDA), kainate, and α-2-amino-3- [hydroxy-5-methylisoxazole-4yl] receptors and are associated with nociceptive transmission at fast excitatory synapses within the dorsal horn and the TNG. Postsynaptic excitation results from the influx of extracellularcalcium ions after glutamate binding of the ionotropic receptors.

Activation of certain metabotropic glutamate receptors (mGluR) by either glutamate or substance P results in the release of calcium from intracellular stores (Mayer and Miller 1990). The increase in intracellular calcium activates protein kinase C, which in turn, through NMDA receptor phosphorylation, causes displacement of the Mg2+ ion that normally blocks the NMDA receptorlinked ion channel. After displacement of the Mg22+ ion, the binding of glutamate to the NMDA receptor at resting membrane potentials results in inward Na+ and Ca2+ currents and increased excitation of the postsynaptic neuron (Mayer et al., 1984).

Although substance P also activates these metabotropic glutamate receptors, higher intensities of stimulation are needed to affect its release from prejunctional neurons (Bausbaum, 1999) than are required to cause prejunctional glutamate release. Although NMDA receptors have a fast excitatory response, NMDA receptor antagonists thus far have not been shown to reduce afferentexcitation or to block acute nociception (Chaplan et al., 1997).

Second-order neurons within the TNC project and transmit nociceptive information to numerous subcortical sites, including the more rostral portionsof the trigeminal complex (Stewart and King, 1963; Jacquin et al., 1990), the hypothalamus (Malick and Burstein, 1998), the nucleus of the solitary tract (Marfurt and Rajchert, 1991), the brain stem reticular formation (Renehan et al., 1986), the midbrain and pontine parabrachial nuclei (Bernard et al., 1989; Hayashi and Tabata, 1990), and the ipsilateral cerebellum (Huerta et al., 1983; Mantle St. John and Tracey, 1987).

The TNC also sends projections to the ventrobasal thalamus (Huang, 1989; Jacquin et al., 1990; Kemplay and Webster, 1989; Mantle St. John and Tracey, 1987), the posterior thalamus (Peschanski et al., 1985; Shigenaga et al., 1983), and the medial thalamus (Craig and Burton, 1981). Nociceptive information is transmitted from the rostral brain stem to other areas of the brain (e.g., the limbic areas) that are thought to be involved in the emotional and vegetative responses to pain (Bernard et al., 1989).

Although it has been difficult to demonstrate areas of direct cortical activation after meningeal stimulation (Goadsby et al., 1991), there is increasing proof that trigeminothalamo-cortical projections exist (Barnett et al., 1995). Most of the information relating to cerebral cortical activation in headache comes from functional blood-flow imaging studies performed in humans during unilateral headache attacks. In one study that employed positron emission tomography (PET), activation in the cingulate cortex and in the auditory and visual association areas was observed several hours into spontaneous unilateral attacks of migraine without aura (Weiller et al., 1995).

These areas of increased cortical blood flow resolved after the headache was effectively treated with an abortive agent. Functional activation in the cingulate gyms also occurs in other painful conditions and is related to the arousal, motor, and affective components of pain (Kwan et al., 2000). In another series of studies employing PET, areas of increased blood flow were seen in the anterior cingulate and insular cortices after activation of VI C fibers using a subcutaneous injection of capsaicin into the forehead (May et al., 1998).

It has been hypothesized that two distinct populations of cortical neurons exist: one receives projections from the ventrobasal complex of the thalamus and subserves localization and discrimination of pain, and the other, which arises from the medial thalamus, is involved in the affective response to pain. The medial thalamus may participate in the transmission of both the discriminative and affective components of pain (Bushnell and Duncan, 1989), suggesting that these two pathways may not be distinct.

Information related to nociception can be modulated at sites extending from the TNC to the cortex. Modulation of the nociceptive signal, both sensitizing and suppressive, is likely to be very important in determining both the clinical features and the potential treatment of headache syndromes.

Central Sensitization and the Trigeminal System
Activation of nociceptive primary afferent fibers increases the excitability of higher-order neurons within the TNC (Burstein et al., 1998). In nontrigeminal pain models, depolarization of C fibers with chemical and inflammatory stimuli has resulted in several state changes. These include expansion of receptive field size (Woolf and King, 1990), lowering of thresholds for second-order neuronal activation in the dorsal horn (Woolf, 1984), recruitment of inputs from normally non-nociceptive fibers (Woolf and King, 1990), and heightened response to suprathreshold stimuli. Collectively, these changes are referred to as “central sensitization” and are reflected clinically in the pain-associated phenomena of spread of cutaneous sensitivity to uninjured areas, hyperalgesia (lowered pain threshold), and cutaneous allodynia (generation of a painful response by normally innocuous stimuli).

Features of central sensitization are observed in headache syndromes and probably contribute to the intensification and prolongation of head pain. For example, migraine pain frequently expands, as the headache develops, to involve half or at times the whole head. In addition, small, usually innocuous head movements (e.g., coughing or straining) become painful during and in the hours after resolution of a migraine attack. Chemical stimulation of nociceptors within the meninges lowers the activation threshold of second order neurons to low-intensity mechanical and thermal stimuli (Burstein et al., 1998).

In addition, noxious chemical dural stimulation lowers the threshold for generation of cardiovascular responses (such as blood pressure elevation) by previously innocuous skin stimulation (amamura et al., 1999). Evidence of central sensitization may be seen in humans as well. In a recent study of 42 migraine patients, repeated measurements of mechanical and thermal pain thresholds were performed in periorbital and forearm skin during and between acute headache attacks; 79% of subjects exhibited cutaneous allodynia (Burstein et al., 2000).

Central Inhibitory Modulation Of Trigeminal Nociception
Modulation within the central nervous system may be inhibitory as well. Defects of the intrinsic inhibitory system may also be important in the clinical evolution of chronic headache disorders. Within the TNC, the nociceptive signal can be modulated by inhibitory interneurons, within lamina II by projections from more rostral trigeminal nuclei (Kruger and Young, 1981) and the nucleus raphae magnus (Sessle et al., 1981), as well as by descending cortical inhibitory systems (Sessle et al., 1981; Wise and Jones, 1977).

Inhibitory GABAergic and enkephalinergic interneurons are likely to act not only on projection neurons (Fields and Basbaum, 1994) but also on the glutamate-containing terminals of primary afferent neurons, where they affect presynaptic inhibition (Iliakis et al., 1996). The most powerful descending inhibitory system is likely to involve projections from insular cortical and hypothalamic areas through the periaqueductal gray matter, and rostral ventral medial medulla to the superficial lamina of the TNC and the upper cervical dorsal horn (Messlinger and Burstein, 2000; Fields and Basbaum, 1994). Stimulation of the periaqueductal gray matter (Morgan et al., 1992), rostral ventral medial medulla (Lovick and Wolstencroft, 1979), areas of somatosensory cortex (Chiang et al., 1990), and hypothalamus (Rhodes and Liebeskind, 1978) suppresses nociceptive responses. The inhibitory interneurons within lamina II of the TNC receive input from descending excitatory serotonergic neurons from the periaqueductal gray matter and rostral ventral medial medulla (Fields and Basbaum, 1994).

Morphine administration increases the release of serotonin in the superficial lamina of the TNC and decreases presynaptic release of substance P. This is consistent with the hypothesis that morphine may activate the 5-hydroxytryptamine -mediated inhibition of nociception in the TNC and dorsal horn (Yonehara et al., 1990). Parabrachial areas (ventrolateral nuclei) also have direct and bilateral projections to all the subnuclei of the trigeminal brain stem nuclear complex (Yoshida et al., 1997). Stimulation of the parabrachial area suppresses both spontaneous and evoked firing in TNC nociceptive neurons (Chiang et al., 1994).

The neuroanatomical substrates of head pain are quite complex and still incompletely characterized. Headaches appear to develop through a cascade of events that are modulated by both suppressive and sensitizing systems. Derangement in these modulatory systems may underlie the development of chronic headache syndromes. A greater understanding of the functional anatomy and physiology of head pain holds the key to more specific and effective treatments.


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F Michael Cutrer
Editors: Silberstein, Stephen D.; Lipton, Richard B.; Dalessio, Donald J.

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