Development Of Nociceptors

Sensory neurons are known to be overproduced during development, and in the immediate prenatal period many DRG cells undergo programmed cell death (apoptosis). There is considerable evidence that sensory neurons compete for a trophic substance in the periphery, and those that fail to obtain adequate levels of such a substance are the ones that do not survive. In the case of nociceptive neurons the trophic substance is nerve growth factor (NGF), and small-diameter neurons express the high-affinity receptor trkA for NGF. If NGF is experimentally depleted, fewer than normal nociceptors survive. In the rat the dependence of nociceptors on NGF for survival lasts until about postnatal day 2.

Nociceptors continue to require NGF beyond postnatal day 2 for at least some functions. Their response to noxious heat is substantially reduced if NGF levels are decreased by chronic treatment with an NGF antibody or with an immunoadhesin molecule, trkA-IgG, that binds endogenous NGF. Another indication of trophic support of nociceptors by NGF emerges from the restoration of function when it is provided to axotomized nociceptors. For example, the TTX-resistant Na current and the SNS/PN3 channel both decline in nociceptor somata after peripheral axotomy, and these can be partially restored by the administration of NGF to the cut proximal nerve stump. Similar findings have been made with regard to SP and CGRP expression in these nociceptors.

The dependence of certain nociceptive functions on NGF in postnatal animals implies that nociceptors continue to express the trkA receptor. However, it has been demonstrated in rats that as the animal develops into a young adult, some nociceptors cease expressing trkA and begin to express the receptor c-ret, for which glial-derived neurotrophic factor (GDNF), a member of the TGF-b superfamily, is a ligand.

In the prenatal rat nociceptive afferents, at least those associated with unmyelinated fibers, exhibit responses to skin stimulation similar to those in the adult even before their central terminals penetrate into the spinal cord gray matter. These afferents send their collaterals into the spinal cord at embryonic day 18-19 (E18-E19), which is somewhat later than cells that will become the large nonnociceptive afferents (E15-E16). The biochemical markers associated with nociceptive afferents begin to be expressed during this prenatal period. The spinal terminals of small-diameter afferent fibers are restricted to the superficial laminae of the dorsal horn from the time of their arrival into the cord, as they are in the adult. However, in the first postnatal week, C-fiber volleys are unable to elicit discharges in dorsal horn neurons. After postnatal day 10, activation of C-fibers elicits the same responses as in adult cord, specifically the windup indicative of the rapid component of central sensitization, and activation of immediate early genes, i.e., c-fos. Thus, in the rat the nociceptive system activated by C-fibers is not an effective sensory system until the second postnatal week.

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