Neuroanatomy of the pain system and of the pathways that modulate pain

Abstract

We review many of the recent findings concerning mechanisms and pathways for pain and its modulation, emphasizing sensitization and the modulation of nociceptors and of dorsal horn nociceptive neurons. We describe the organization of several ascending nociceptive pathways, including the spinothalamic, spinomesencephalic, spinoreticular, spinolimbic, spinocervical, and postsynaptic dorsal column pathways in some detail and discuss nociceptive processing in the thalamus and cerebral cortex. Structures involved in the descending analgesia systems, including the periaqueductal gray, locus ceruleus, and parabrachial area, nucleus raphe magnus, reticular formation, anterior pretectal nucleus, thalamus and cerebral cortex, and several components of the limbic system are described and the pathways and neurotransmitters utilized are mentioned. Finally, we speculate on possible fruitful lines of research that might lead to improvements in therapy for pain.

FIG. 1.

Sensitization of a “silent” C-nociceptor supplying the knee joint. A and B: Left: Absence of responses to flexion of the knee or to innocuous (OR) and noxious (n.OR) outward rotation of the knee in a cat before initiation of experimental arthritis by injection of kaolin and carrageenan into the knee joint. At this time, no receptive field could be demonstrated in the joint by mechanical probing (C: Left). Middle (A-C): A response to flexion and noxious outward rotation of the knee and a receptive field to probing the joint developed by 90 min after initiation of inflammation. The responses continued to increase (A and B: Right). The response to stimulation of the receptive field is shown in C (right). (Reprinted fromSchaible and Schmidt, 1988, with permission.)

FIG. 2.

Peristimulus time histogram showing the response of afferent fibers in the medial articular nerve of a rat to intraarticular injection of glutamate. A dose of 0.1 ml of a 1-nM solution of glutamate was injected into the knee joint at the time indicated by the arrow. (From Lawand, W. D. Willis and K. N. Westlund, unpublished observations).

FIG. 3.

Changes in glutamate and peptide content in the dorsal horn during the development of experimental arthritis.Top: The photomicrographs show a section of the lumbar dorsal horn 24 h after the induction of arthritis by injection of kaolin and carrageenan into the capsule of the knee joint. The section is immunohistochemically stained for glutamate, which is increased on the inflamed side(left) as compared with the normal side (right).Bottom: The bar graphs in A-C show the changes in immunoreactivity of the dorsal horn for glutamate, substance P, and calcitonin gene-related peptide at different times after the induction of arthritis. Lumbar spinal cord (left). Staining density in the cervical spinal cord did not change (right). *Statistically significant changes. (From Sluka and Westlund, 1993.)

FIG. 4.

Increased responses of a primate spinothalamic tract cell after acute arthritis was induced by injection of kaolin and carrageenan into the knee joint. Top: Receptive field of the neuron on the ankle and foot before (doubly hatched area) and after(hatched area) the development of arthritis. Left columns: Peristimulus histograms show the background activity of the neuron and its responses to flexion of the knee, to brushing the skin at the points labeled 1–5 in the drawing, and to pinching the skin at the same points. Right columns: Histograms show the enhanced background activity and response after the development of arthritis. The increased background activity would presumably result in pain in an unanesthetized animal, and the increased response to knee flexion would be an indication of primary hyperalgesia. The increased responses to stimulation of the foot would presumably represent secondary mechanical allodynia and hyperalgesia. (From Dougherty et al., 1992b.)

FIG. 5.

Inhibition of a primate spinothalamic tract cell by baclofen administered in the spinal cord by microdialysis. A: Background activity of the neuron is shown before and during the administration of the GABAB receptor agonist baclofen and (left) right during the coadministration of baclofen and the GABAB receptor antagonist, phaclofen (right).B: Responses of the cell to brush, pinch, and heat stimuli applied to the receptive field before and during baclofen administration and during coadministration of baclofen and phaclofen. C: Antidromic and orthodromic action potentials of the neuron at different times during the experiment. (From Lin et al., 1996c.)

FIG. 6.

Course of the laterally projecting component of the spinothalamic tract in a macaque monkey. The cells of origin of the part of the spinothalamic tract that projects to the lateral thalamus are concentrated in laminae I and V of the spinal cord dorsal horn. The axons cross the midline in the ventral gray commissure at a level near that of the cell bodies of the neurons. The axons then ascend in the ventral and then in the ventrolateral quadrant. After passing through the brainstem, the axons terminate synaptically in the lateral thalamus. The nuclei of termination include the caudal part of the ventral posterior lateral nucleus (VPLc) and also the ventral posterior inferior (VPI) and the medial part of the posterior group (POm; data not shown). Some of the laterally projecting spinothalamic tract neurons send collaterals to the medial thalamus, where they end in the central lateral(CL) nucleus (dashed lines).

FIG. 7.

Course of the medially projecting component of the spinothalamic tract of a macaque monkey. The cells of the spinothalamic tract that project just to the intralaminar nuclei of the medial thalamus originate in the deep dorsal horn and the ventral horn of the spinal cord. The axons decussate immediately and then ascend in the ventral and then in the ventrolateral white matter. After passing through the brainstem, they terminate in the intralaminar nuclei, especially the central lateral (CL) nucleus.

FIG. 8.

Course of the spinomesencephalic tract in a macaque monkey. The cells of origin of the tract are concentrated in laminae I and V. The axons decussate in the ventral white commissure and ascend to the midbrain in the lateral funiculus. They end in several midbrain nuclei, including the periaqueductal gray (PAG) and cuneiform nucleus(CUN).

FIG. 9.

Course of the component of the spinoreticular tract that projects to the caudal reticular formation in a macaque monkey. The cells of origin are concentrated in the ventral horn in laminae VII and VIII. The axons decussate and ascend in the lateral funiculus and terminate in several nuclei of the reticular formation of the medulla and pons, including the nucleus gigantocellularis (NGc).

FIG. 10.

Course of the component of the spinoreticular tract that projects to the parabrachial region. The spinoreticular neurons are in the dorsal horn, including laminae I and V, and project to several nuclei in the parabrachial region, including the locus ceruleus, the Kölliker-Fuse nucleus, and the parabrachial nuclei.

FIG. 11.

Spinoreticular projection with connections to brainstem catecholamine cell groups. Sagittal sections of a monkey brainstem are shown from the side contralateral to an injection site in lamina I of the cervical spinal cord where an anterograde tracer was placed. The catecholamine cell groups (A1, A2, A5, A6, A7, C1; open circles) were demonstrated by immunocytochemical staining for tyrosine hydroxylase. Locations of the terminals of spinal projection neurons (small dots). (From Westlund and Craig, 1996.)

FIG. 12.

Course of spino-limbic projections in the rat. Neurons in the dorsal horn and also in the region of the central canal project through the lateral funiculus to the hypothalamus(HYP), amygdaloid nucleus (AMY), and the septal nuclei (SN).

FIG. 13.

Course of the component of the postsynaptic dorsal column pathway that may mediate visceral pain. The afferent input to the sacral spinal cord from a pelvic visceral organ is shown by a drawing of a dorsal root ganglion cell and its peripheral and central processes. The afferent connects with a circuit that activates a projection neuron located in the central gray region (lamina X). The projection neurons sends its axon rostrally near the midline of the dorsal column to synapse in the nucleus gracilis. The gracile neuron projects to the contralateral ventral posterior lateral (VPL) nucleus in the thalamus.Left: Procedure for a limited midline myelotomy to interrupt this visceral pain pathway (H. J. W. Nauta, E. Hewitt, K. W. Westlund, W. D. Willis, unpublished observations).

FIG. 14.

Descending analgesia systems. Two projection neurons in the spinal cord dorsal horn that receive descending inhibitory synapses (minus signs) from brainstem neurons are shown. The descending axons originate in the nucleus raphe magnus (NRM) and the locus ceruleus (LC) and adjacent nuclei of the parabrachial region. The periaqueductal gray (PAG) is shown to have excitatory connections (plus signs) to the NRM and LC.