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Central mechanisms in chronic pain

Created: 6/9/2005
Updated: 12/1/2009

Following a peripheral nerve injury, anatomical and neurochemical changes can occur within the central nervous system (CNS) that can persist long after the injury has healed. This "CNS plasticity" may play an important role in the evolution of chronic, neuropathic pain. As is the case in the periphery, sensitisation of neurones can occur within the dorsal horn following peripheral tissue damage, and this is characterised by an increased spontaneous activity of the dorsal horn neurones, a decreased threshold and an increased responsivity to afferent input, and cell death in the spinal dorsal horn.

In the non-injured state, A-beta fibres penetrate the dorsal horn, travel ventrally, and terminate in lamina III and deeper. C fibres penetrate directly and generally terminate no deeper than lamina II. However, after peripheral nerve injury there is a prominent sprouting of large afferents dorsally from lamina III into laminae I and II. After peripheral nerve injury, these large afferents gain access to spinal regions involved in transmitting high intensity, noxious signals, instead of merely encoding low threshold information.

Significant alterations have been shown in the dorsal horn ipsilateral to the injury. The mechanisms are likely related to the barrage of afferent impulses or the factors transported from the lesion site. Studies have revealed that peripheral nerve injury may lead to increased mRNA for specific neurotransmitters (e.g. substance P), differential temporal expression of mRNA and receptors, decreased levels of opioid binding sites and the appearance of immediate early gene products (e.g. c–fos). The significance of this is possibly that peripheral nerve injury is causing changes in the cell's synthesis of products, and alterations in the relative levels of neuropeptides/neuromodulators (e.g. increased galanin and VIP and reductions in substance P and calcitonin gene related peptide).

Figure showing substance P activity

Several forms of thermal or tactile hyperalgesia may involve the intercellular and intracellular messengers nitric oxide and arachidonic acid and metabolites. Cyclooxygenase inhibition appears to suppress tactile allodynia. Blockade of activation of protein kinase C has been shown to prevent behavioural neuropathic manifestations. Protein kinase C removes the voltage gating of the NMDA (N-methyl-D-aspartate) receptor, allowing activation of the receptor by glutamate. Protein kinase C may also modulate sodium channels.

The injured axon may release factors which may be transported in a retrograde or orthograde fashion to initiate changes important to the development of a pain state.

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