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The induction of pain: an integrative review

THE central terminals of primary afferent neurons are topographically highly ordered in the spinal cord1 Peripheral receptor sensitivity is reflected by dorsal horn laminar location: low-threshold mechanoreceptors terminate in laminae III and IV (refs 2, 3) and high-threshold nociceptors in laminae I, II and V (refs 4, 5) Unmyelinated C fibres, most of which are nociceptors6, terminate predominantly in lamina II (refs 5,7) There is therefore an anatomical framework for the transfer of specific inputs to localized subsets of dorsal horn neurons This specificity must contribute to the relationship between a low-intensity stimulus and an innocuous sensation and a noxious stimulus and pain We now show that after peripheral nerve injury the central terminals of axotomized myelinated afferents, including the large Aβ fibres, sprout into lamina II This structural reorganization in the adult central nervous system may contribute to the development of the pain mediated by A-fibres that can follow nerve lesions in humans8,9

Peripheral nerve injury triggers central sprouting of myelinated afferents

Although spontaneous regeneration of lesioned fibres is limited in the adult central nervous system, many people that suffer from incomplete spinal cord injuries show significant functional recovery. This recovery process can go on for several years after the injury and probably depends on the reorganization of circuits that have been spared by the lesion. Synaptic plasticity in pre-existing pathways and the formation of new circuits through collateral sprouting of lesioned and unlesioned fibres are important components of this recovery process. These reorganization processes might occur in cortical and subcortical motor centres, in the spinal cord below the lesion, and in the spared fibre tracts that connect these centres. Functional and anatomical evidence exists that spontaneous plasticity can be potentiated by activity, as well as by specific experimental manipulations. These studies prepare the way to a better understanding of rehabilitation treatments and to the development of new approaches to treat spinal cord injury.

Plasticity of motor systems after incomplete spinal cord injury

The neural basis of perceptual learning.

Removal of sensory input from a focal region of adult neocortex can lead to a large reorganization of cortical topography within the deprived area during subsequent months. Although this form of functional recovery is now well documented across several sensory systems, the underlying cellular mechanisms remain elusive. Weeks after binocular retinal lesions silence a corresponding portion of striate cortex in the adult cat, this cortex again becomes responsive, this time to retinal loci immediately outside the scotoma. Earlier findings showed a lack of reorganization in the lateral geniculate nucleus and an inadequate spread of geniculocortical afferents to account for the cortical reorganization, suggesting the involvement of intrinsic cortical connections. We investigated the possibility that intracortical axonal sprouting mediates long-term reorganization of cortical functional architecture. The anterograde label biocytin was used to compare the density of lateral projections into reorganized and non-deprived cortex. We report here that structural changes in the form of axonal sprouting of long-range laterally projecting neurons accompany topographic remodelling of the visual cortex.

Axonal sprouting accompanies functional reorganization in adult cat striate cortex.

We have studied the ability of primary afferent neurones to proliferate within the grey matter of the dorsal horn following the degeneration of other, nearby, afferent fibres. The peripheral branches of primary afferents have the capacity to regenerate successfully over long distances, and we have examined the possibility that when they are so doing, the neurones' status changes to facilitate greatly the sprouting of afferent fibres within the dorsal horn.



“Spared root” preparations (rhizotomies of L3, L4, L6, S1, and the caudal half of L5, sparing the rostral half of the L5 dorsal root) were made in adult rats. In some animals (acute preparations) the distribution of the central terminals of the spared root was assessed by labelling the sciatic nerve with WGA-HRP at the time of the rhizotomies. In other animals (chronic preparations, symmetrical bilateral spared roots were made and the sciatic nerve on one side was concomitantly crushed to trigger regrowth of the peripheral branches of these axons. Eight to 10 weeks later the sciatic nerves on both sides were labelled with HRP-WGA.



In the acute preparations the reaction product was found in a limited rostrocaudal and mediolateral region of the dorsal horn. In lamina II (the lamina of densest labelling the labelled terminals occupied an average of 1.17 ± 0.21 mm2. In chronic preparations, the area of labelled terminals on the side of the uncrushed sciatic nerve was 1.34 ± 0.28 mm2 (not significantly different from acute animals). However, the labelled area on the side of the crushed sciatic nerve was significantly greater, averaging 2.17 ± 0.14 mm2. Hence, primary afferent nerve fibres show greatly enhanced sprouting within the grey matter of the dorsal horn of the spinal cord when two conditions are fulfilled; 1) vacant synaptic sites are created by the degeneration of other primary afferent fibres; and 2) the peripheral branches of the axons are actively regenerating.

Rupert Kett‐White

Papers

Sprouting of peripherally regenerating primary sensory neurones in the adult central nervous system.