Pain-Sensitive Cranial Structures: Chemical Anatomy
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.