Objectif
The majority of nociceptive primary sensory neurons (PSN) express vanillin receptor 1 (VR1). In physiological conditions Varies activated by heat above ~42°C resulting in acute burning sensation. In pathological conditions VR1 is activated by normal body temperature initiating the development of prolonged and chronic burning pain sensation, which often accompanies diseases, such as diabetes mellitus (DM). The reduction in the heat threshold of VR1 is produced by post-transactional modification of VR1. Our recent data suggest that insulin; a key regulator of metabolism could initiate such modification of VR1. Insulin reduces the blood' s glucose concentration and failure of this action results in DM. In one form of DM insulin cannot reduce the blood' s glucose concentration as its signalling system is dysfunctional, which is overcome by higher production of, while at a later stage by high amounts of exogenous, insulin. Based on our pilot data, we hypothesize that high insulin levels might contribute to the development of burning pain associated with some types of DM. In the proposed experiments first, by using combined immunoassaying we will study whether the molecular basis for insulin-induced modification of VR1, the co-expression of the receptor for insulin and VR1 exists on PSN. Than, by recording from in vitro skin-nerve preparations, and acutely isolated and cultured PSN we will elucidate whether or not insulin is able to activate VR1-expressing PSN. Next, we will measure whether insulin can induce transmitter release from PSN in the spinal cord. Finally, we will find out the molecular mechanisms underlying the insulin-induced activation of VR1. To prove that the insulin-induced effects are mediated through VR1 the experiments will be done on mice from which the gene encoding VR1 will be deleted. Results of these studies will lead to a better understanding and treatment of burning pain sensation developing in certain types of DM.
Champ scientifique
Appel à propositions
FP6-2002-MOBILITY-5
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Régime de financement
EIF - Marie Curie actions-Intra-European FellowshipsCoordinateur
LONDON
Royaume-Uni