Unique Anatomical And Biochemical Properties Of Nociceptors

Although the cell bodies of nociceptors and low-threshold mechanoreceptors are located in the sensory ganglia [the dorsal root ganglion (DRG)] or similar structures for cranial nerves (e.g., the gasserian ganglion of the trigeminal nerve), they exhibit numerous differences in their projections and in their chemistry that determine their properties as nociceptors (Fig. 1). All of these contribute to the basic characteristics of nociceptors and nociceptive pathways, including their high threshold and their ability to be sensitized after certain types of stimuli.

From the early functional studies indicating that axons of nociceptors are among the smallest in peripheral nerves, it was believed that the cell bodies of nociceptive afferents would be among the smallest, and this has been confirmed with correlative electro-physiological and anatomical studies of individual sensory neurons. However, there is considerable scatter in soma size for axons of a particular group (e.g., Ad-axons), making soma size somewhat less reliable as an indicator of nociceptive vs nonnocicep-tive neurons than axon size. Nonetheless, many workers have considered a soma diameter of 30 mm to be a dividing line below which the population is highly enriched in nociceptors.

Various markers have been found to correlate with cell size, and thus putatively to correspond to cells with nociceptive and nonnociceptive function. Many investigators have divided the dorsal root ganglion cell

Figure 1 Chemical specialization of nociceptive sensory neurons that distinguishes them from nonnociceptive afferents. These specializations are divided into activators and sensitizing agents, receptors, Na channels, and released substances. In the latter group, glutamate is not unique to nociceptive afferents, but as discussed in the text it activates specialized glutamate receptors that result in the unique central action of nociceptors.

Figure 1 Chemical specialization of nociceptive sensory neurons that distinguishes them from nonnociceptive afferents. These specializations are divided into activators and sensitizing agents, receptors, Na channels, and released substances. In the latter group, glutamate is not unique to nociceptive afferents, but as discussed in the text it activates specialized glutamate receptors that result in the unique central action of nociceptors.

population into small dark and large light cells on the basis of their appearance in Nissl-stained sections. The large light cells stain with RT-97, an antibody against the phosphorylated form of the 200-kDa neurofilament subunit, whereas the small dark ones do not. Cells staining with RT-97 are believed to have myelinated axons ranging over the entire size spectrum (Ab and Ad).

A number of biochemical labels are present only in small somata and, thus, presumptively those that are nociceptors. These markers include the lectin IB4, the enzyme fluoride-resistant acid phosphatase (FRAP), trkA (the high-affinity receptor for NGF), c-ret (the receptor for glial-derived neurotrophic factor, GDNF), and various peptides such as substance P (SP), calcitonin gene-related peptide (CGRP), and somatostatin. However, none of these markers is present in the entire population of small cells, and some such as CGRP are also present to some degree in larger cells. Thus, the population of small DRG neurons is quite varied in its expression of these and other markers. Loss of specific functional capacity when a specific gene is eliminated, i.e., in "knockout" mice, suggests that the expression of some of these markers corresponds to specific psychophysical modalities, e.g., substance P expression relates to the ability to sense very intense thermal stimuli.

Although small DRG cells are highly varied in their expression of FRAP, substance P, etc., some of these markers tend to be frequently coexpressed, whereas others are coexpressed very infrequently. For example, c-ret, IB-4, and FRAP tend to be coexpressed and these cells do not express peptides. Another group of cells expresses trkA as well as peptides such as CGRP and/ or substance P. The population of cells coexpressing markers in these different groups is relatively small. The trkA/peptide-expressing cells include some with small myelinated and some with unmyelinated axons, whereas the IB4/c-ret/FRAP-expressing neurons have largely, if not exclusively, unmyelinated axons.

Nociceptive neurons are also unique in their projection into the central nervous system. Numerous evaluations of their termination sites, including the location of peptide-expressing terminals as well as the transport of various materials such as horseradish peroxidase (HRP) in physiologically identified noci-ceptive afferents impaled at the dorsal root entry zone, have demonstrated that they terminate largely though not exclusively in the most superficial laminae of the dorsal horn. Small myelinated nociceptive afferents terminate in lamina I (also known as the marginal zone) and lamina V (the deepest part of the nucleus proprius), whereas unmyelinated afferents terminate in lamina II.

Many workers have subdivided lamina II into inner and outer portions (lamina IIo and lamina II;). The IB4/c-ret/FRAP-expressing neurons terminate largely in lamina II;, whereas the peptide-containing neurons terminate in laminae IIo and I. Physiological evidence suggests that cells in lamina IIi respond almost exclusively to nonnoxious stimulation. This would indicate that the afferent population projecting into this zone responds to nonnociceptive stimuli. However, many IB4-expressing neurons express the receptor for capsaicin (VR1), which would suggest that they are responsive to noxious heat and chemical stimulation, specifically protons. This apparent discrepancy remains to be resolved, but it is important to recall that, in this as in other studies, the recordings from central neurons were made in reduced preparations where their properties may be distorted.

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