Obiettivo
One of the most intriguing problems of contemporary neuroscience is that of chronic pain in those circumstances in which there is no evidence of ongoing noxious stimulation. We have advanced the hypothesis that a process similar to learning and memory in pain modulating systems may be important in the development of chronic pain. This hypothesis is based on a finding we made in our Concerted Action BIOMED 1 project "Mechanisms of chronic pain" of long-term potentiation (LTP) in wide dynamic response (WDR) cells in the spinal dorsal horn of rats after a painful electrical stimulation of the sciatic nerve. The excitability of the WDR cells was increased by 50-100 %, and remained at the same high level for the 6 hours the experiment lasted. Previously LTP has been observed in intracellular recordings in-vitro or in field potentials, and short lasting signs of central sensitization like wind-up have been reported by many researchers. Our finding is, however, the first observation of LTP in extracellular recordings from single cells in intact animals. The duration of the phenomenon seems to be sufficiently long to be a possible basis for the development og chronic pain. The model is suitable both for the investigation of the mechanisms of increased excitability and for the testing of substances with analgesic properties.
The finding was of such great interest for a new therapeutic strategy for chronic pain and the development of new analgesic drugs that a partnership of five research groups was formed with the aim to investigate the detailed mechanisms of the increased excitability of the WDR cells and the plasticity of cell communication and pain modulation in the dorsal horn and in the trigeminal system. A multi-disciplinary expert group has been assembled, all of international standing and including neurophysiologists, neuroanatomists, neuropharmacologists and a pharmaceutical company, all with specific expertise in pain control.
As a basis for the work, the LTP model will be described in detail. Intracellular mechanisms in the WDR cells related to the LTP development, as well as changes in neuroreceptors and dorsal horn release of neurotransmitters using advanced microdialysis techniques, and the role of facilitatory and inhibitory supraspinal influences, will be studied. The special anatomical structure of the part of the trigeminal system that has the same function as the dorsal horn, offers a unique possibility of studying the effect on LTP of drugs applied by micro-injection or microdialysis. Validation of the relevance of the model to nociception will be done in studies in awake animals. Throughout the whole project, ways of inhibiting LTP will be particularly investigated.
A main goal of the project is to facilitate the development of new analgesic drugs with fewer side effects than those available today. When details of the mechanisms of LTP in the WDR cells are known, Astra will synthesise substances specifically designed to inhibit the induction and/or the maintenance of LTP. The testing of these substances will be part of all Work Packages, and a continuous interaction between Astra and the other partners will take place. The participation of a pharmaceutical company as a partner in a central role assures the immediate transfer of relevant findings to applied research and the development of drugs to be used in patients. The LTP model itself should be of great interest both as a research tool for other research groups, and for the pharmaceutical industry for the testing of substances.
The project closely fits both the general and some of the specific aims of the BIOTECHNOLOGY work programme Area 4.4. It requires a multi-disciplinary effort by several research groups with complementarity of the partners and gains added value from its European dimension. The future aim of the project is the reduction of chronic pain, disorders that have vast social and economic consequences for the European Community as well as being a main cause of human suffering.
Campo scientifico (EuroSciVoc)
CORDIS classifica i progetti con EuroSciVoc, una tassonomia multilingue dei campi scientifici, attraverso un processo semi-automatico basato su tecniche NLP. Cfr.: Il Vocabolario Scientifico Europeo.
CORDIS classifica i progetti con EuroSciVoc, una tassonomia multilingue dei campi scientifici, attraverso un processo semi-automatico basato su tecniche NLP. Cfr.: Il Vocabolario Scientifico Europeo.
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Coordinatore
5009 Bergen
Norvegia
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