Descripción del proyecto
Información sobre el mecanismo del dolor crónico
Las neuronas sensitivas periféricas de la piel, conocidas como nocirreceptores, nos alertan de los estímulos potencialmente dañinos al detectar señales o responder a las sustancias químicas del tejido dañado. Los nocirreceptores transforman estos estímulos en señales eléctricas en el encéfalo, lo que provoca la sensación de dolor. El objetivo del proyecto SCOPE, financiado con fondos europeos, es abordar la limitada eficacia de los medicamentos analgésicos existentes contra el dolor crónico asociado al cáncer y las neuropatías de origen central. Sus investigadores se centrarán en el canal iónico de potencial receptor transitorio, de tipo anquirina 1 (TRPA1), que se expresa en las células de Schwann y está implicado en el dolor agudo. La idea es investigar el papel del eje TRPA1-células de Schwann en el dolor crónico y determinar posibles nuevas dianas farmacológicas.
Objetivo
Chronic pain, characterized by increased sensitivity to innocuous/mild stimuli (allodynia), afflicts 25% of the European adult population. Efficacy and/or safety of analgesic medicines is limited, and the treatment of chronic pain associated with inflammation, peripheral and central neuropathies and cancer remains unsatisfactory. Thus, identification of novel targets for better and safer analgesics is a major medical need. Transient receptor potential ankyrin 1 (TRPA1) channel, expressed by a subpopulation of primary sensory neurons (nociceptors), has been proposed as a major transducer of acute pain. We have, recently, identified that TRPA1 is expressed in Schwann cells that ensheath peripheral nerve fibres. In a prototypical model of neuropathic pain (sciatic nerve ligation in mice), we discovered that Schwann cell-TRPA1 exerts a hitherto unknown role that, via amplification of the oxidative stress message, sustains neuroinflammation and chronic pain (allodynia). Thus, Schwann cells, through their own repertoire of channels and enzymes orchestrate in the injured/inflamed tissue an autocrine/paracrine signalling pathway to sustain chronic pain. The purpose of the present project is to extend this observation to other models of inflammatory, neuropathic and cancer pain to identify a general paradigm based on Schwann cell/TRPA1/oxidative stress as the pathway that sustains chronic pain. We aim also at identifying in oligodendrocytes (the Schwann cells of the brain) whether the TRPA1/oxidative stress pathway sustains pain in the central nervous system. In mouse, rat and human Schwann cells/oligodendrocytes we aim at identifying biomarkers and combine them into biosignatures predictive of the susceptibility to the development of chronic pain. We anticipate that each molecular step that entails the TRPA1/oxidative stress pathway in Schwann cell lineages is an eligible target for discovering new effective and safer medicines for the treatment of chronic pain.
Ámbito científico
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Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
50121 Florence
Italia