Plasticity Of Nociceptors

One of the hallmarks of nociceptors and the nocicep-tive pathway is their susceptibility to change in response to various alterations in their environment (Fig. 5). Inflammation in the periphery can result in a diminished threshold to noxious stimuli. In part this reflects the action of various substances in the "inflammatory soup'' (see Section VIII.A). However, there are also changes in properties of the nociceptor itself, such that it responds differently to components of the inflammatory soup. For example, the response of individual nociceptive afferents to capsaicin can be enhanced if NGF or PGE2, known to sensitize individual nociceptors, is applied to the neuron. Thus, sensitization at the level of the periphery is thought to represent a change in the sensitivity of the receptor itself, in this case quite possibly a change in the phosphorylation state of the capsaicin receptor (i.e., VRl).

A second locus at which nociceptors exhibit plasticity is the cell body. Inflammation in the periphery results in up-regulation of substance P and CGRP as well as the neurotrophin brain-derived neurotrophic factor (BDNF) in nociceptors. The enhanced level of these substances is believed to result in a more intense driving of the postsynaptic cells on which these nociceptors terminate. The peptides act to prolong the depolarization, thereby relieving the Mg block of postsynaptic NMDA receptors and enabling these cells to be more intensely activated. BDNF directly increases the NMDA-receptor-mediated responses and thereby enhances the response of nociceptive neurons of the dorsal horn that are known to express NMDA receptors.

After peripheral inflammation, some large-diameter afferents that are activated by innocuous stimuli can undergo a phenotypic switch and display characteristics of nociceptors, specifically the expression of substance P in their somata. Release of this peptide could result in intensification of the discharge of some central neurons that they activate. Activation of cells in lamina II by large-diameter afferents can be enhanced under these conditions. These changes could contribute to the allodynia that is often reported after inflammatory injury.

Nociceptive afferents also display considerable plasticity when their axons are cut in the periphery. The level of some peptides (CGRP, SP) decreases, whereas the level of others (e.g., neuropeptide Y and GAP43) increases. This is thought to reflect, at least in part, the changing metabolic priorities of these neurons from a transmission mode to a regeneration mode. Similar changes occur in nociceptors of aged animals, and this has been shown to reflect diminished neurotrophic support from the periphery, e.g., a

Nociceptor Plasticity in Different States




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