Mechanisms of pain processing: spinal protein translation in the rat.
Doctoral thesis, UCL (University College London).
The word ‘pain’ is described by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Shifts in pain thresholds and responsiveness are an expression of neural plasticity, a process whereby changes in the nervous system modulate the response to a given stimulus. It is widely believed that this process may contribute to chronic pain. Forms of long-term plasticity specifically require protein synthesis and such mechanisms are widely believed to be cellular counterparts of long-term memory. Relevant to mammalian pain nociceptors is the realisation that messenger ribonucleic acid (mRNA) in dendrites, axons, axon terminals as well as cell bodies, is essential for long-term synaptic plasticity and may therefore be important in pain processing. The protein kinase mammalian target of rapamycin (mTOR) is a key regulator of protein translation and can be specifically inhibited by the drug rapamycin and the rapamycin analogue cell cycle inhibitor (CCI)-779 (CCI-779). This was investigated in rats under physiological conditions and also pathophysiological conditions relevant to clinical pain syndromes i.e. persistent pain-like states. A variety of techniques were utilised: in vivo electrophysiology was used to obtain extracellular single unit recordings of spinal cord lamina V wide dynamic range (WDR) neurones that respond to innocuous and noxious stimuli to peripheral sites i.e. the rat hind paw; behavioural studies were used to assess the progression of pain-like states and assess the effects of rapamycin/CCI-779 on this behaviour and immunohistochemistry was used to visualise active components of rapamycin-sensitive protein translation pathways at the spinal level. In addition, the dependence of these spinal mechanisms on descending serotonergic pathways from higher brain centres was investigated pharmacologically by selectively activating or blocking serotonergic spinal 5-HT3 receptors. These pathways have already been proven to be pivotal in the maintenance of persistent pain-like states. The results suggest that mTOR has a continuous role in maintaining persistent pain-like states via rapid local protein translation, which can be influenced by descending facilitatory controls from higher centres in the brain.
|Title:||Mechanisms of pain processing: spinal protein translation in the rat|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||This work was supported by The Wellcome Trust.|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Neuroscience, Physiology and Pharmacology|
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