Central sensitization: according to professor Dickenson

At the third international Congress on neuropathic pain in Athens (NeuPSIG, may 2010) professor Anthony Dickenson gave a nice and crisp talk on central sensitization. Dickenson pointed out that within the spinal cord, a number of changes underlie central sensitization. Whereby the response to a given input is increased by central spinal mechanisms

First step: calcium channel involvement

pixabay-583713-INP Central sensitization

involvement of calcium channels that are essential for transmitter release onto spinal neurons. Gabapentin and Pregabalin act on these changed calcium channels. This increase in transmitter release leads to greater levels of activation of spinal receptors and increased neuronal excitability.

Second step: activation NMDA receptor

In the spinal cord, the release of peptides and glutamate causes activation of the N-methyl-D-aspartate (NMDA) receptor for glutamate in persistent pain states which, in concert with other spinal systems, generates spinal hypersensitivity.

Third step: wind up and LTP

Activation of the NMDA receptor underlies two key processes, 

  • wind-up and 
  • long term potentiation (LTP).

 Fourth step: Wind-up 

Wind-up: This is an increase in neuronal responses to a given constant stimulus – also known as temporal summation. If the input continues, the responses remain elevated. Wind-up is induced by C and A-delta fibre inputs but once produced, enhances all responses, including those to low threshold inputs.

Once the peripheral input declines, there is a slow return in neuronal responses back to baseline. Here, blocking peripheral drives should attenuate central sensitization.

Next: wind-up into LRP 

Professor Dickenson followed with: LTP is a longer lasting version of wind-up where a high frequency C-fibre input now produces hours of excitability. An event that persists even though the input is terminated. Genes that are implicated in memory processes add to the neuronal changes. And many intracellular processes are altered.

Spinal neurons that become hyper excitable show reduced thresholds, increased receptive field sizes and ongoing stimulus independent activity, As well as greater evoked responses. This activity is a likely basis for the allodynias, hyperalgesia and spontaneous pains seen in patients since many of these spinal neurons project to higher centers of the brain.

Ketamine blocks the NMDA receptor complex and use of NMDA antagonists has been a useful tool for demonstration of NMDA receptor mediated hypersensitivity in patients with post-operative, tissue damage, neuropathic and recently, CRPS pains.

Understanding downstream events beyond the surface receptor or designing drugs that act on sub-types of NMDA receptor may improve the clinical acceptability of drugs that block this sensitization.

Source

Oral presentation: C4. Complex Regional Pain Syndrome: From Human Model to the Clinic Abstract: 73 European Journal of Pain Supplements, Volume 4, Issue 1, May 2010, Page 22
CENTRAL SENSITIZATION by A. Dickenson, Neuroscience, University College London, London, UK

Prof. dr. J.M. Keppel Hesselink
‘Central sensitization: according to professor Dickenson’ 

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