EIF-2003-ET/RS · Role of neurosteroids in a novel mechanism modulating the nociceptive system through ATP and GABA receptors
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2004-03-01 → 2006-02-28
- EU contribution
- €149,103
- Participants
- 1
- Scheme
- EIF
Lines connect the coordinator with its partners.
Results in brief
Final Activity Report Summary - EIF-2003-ET/RS (Role of neurosteroids in a novel mechanism modulating the nociceptive system through ATP and GABA receptors)
Transmission of pain signals is essential to maintain the integrity of an organism. Certain diseases however generate chronic, pathological pain, which is detrimental to this integrity. The initial objective of this proposal was to improve our comprehension of the generation of pathological pain and define the role of neurosteroids, i.e. a class of steroids synthesised by the nervous system, in the initiation and transmission of pain signals. Gamma-aminobutiric acid (GABAA) receptor, the major inhibitory receptor in the nervous system, is involved in the control of the transmission of pain signals. We stimulated the production of neurosteroids in cultured sensory neurons with diazepam. Flumazenil was used to block the concurrent binding of diazepam to the benzodiazepine modulatory site located on GABAA receptors. Flumazenil was not considered to have an intrinsic effect on GABAA responses. Surprisingly, the sustained application of flumazenil alone inhibited GABAA responses. This atypical inhibitory effect suggested that our experimental conditions could unveil either: 1. an undescribed pharmacological property of flumazenil, or 2. the presence of an unknown endogenous molecule that stimulated GABAA receptors. Flumazenil could displace this unknown constitutive stimulator, thereby inducing an apparent inhibition of the GABAA response. The project has been refocused on the analysis of the pharmacology of flumazenil in order to analyse this atypical effect. However, despite the use of optimised standardised protocols, the initially reproducible inhibitory effect of flumazenil was lost in later experiments. This raised the probability that physiological parameters, such as the stress level of the organisms, might affect the presence of the unknown modulator or modify the sensibility of cells to flumazenil. This work provided a new view on the pharmacology of flumazenil and its clinical use as a drug reversing the effects of benzodiazepines. In addition to the main project, I participated in a collaborative work studying the mechanisms of the generation of inflammatory pain. We analysed the regulatory factors of the FOS family and the neuronal nitric oxide signalling pathway in the spinal cord and evaluated their synergistic interaction during inflammatory pain. This novel mechanism might constitute a target for innovative therapeutic strategies in the management of chronic or neuropathic pain.
Data: CORDIS, © European Union
Project objective
Nociceptive stimuli are essential in maintaining the integrity of an organism. Certain diseases however generate chronic, pathological pain, which is detrimental to this integrity. P2X ATP receptors are involved in the initiation and transmission of nociceptive signals in peripheral tissues. The host laboratory showed that P2X receptors, as well as GABAA receptors, are involved in a new mechanism modulating nociceptive signals in the spinal cord and that their function can be affected by neurosteroids, a class of steroids produced in the nervous system.This project aims to(1) Determine the exact nature of the endogenous neurosteroids involved in nociception and their site of production(2) Define both the acute and chronic action of these neurosteroids on nociceptive neurotransmission(3) Determine the nociceptive neuronal subpopulations affected by these neurosteroids(4) Evaluate the role of neurosteroids in the generation of pathological pain in disease statesWe will use a multidisciplinary approach including morphological, electrophysiological and molecular methods applied to in vitro and in vivo models of inflammatory or Neutrogena pain. The results of this project will improve our comprehension of the generation of pathological pain and define the role of neurosteroids in the initiation and maintenance of pain. The neurosteroid modulation mechanism of nociceptive signalling will provide targets for new and innovative therapeutic strategies of chronic pathological pain management that avoid side effects such as addiction and tolerance. This project relies on the synergy of the competences of both the fellow and the host laboratory. It will result in a two-way knowledge transfer that will enhance both the career prospects of the fellow and the scientific excellence of the host institution and more generally of the European scientific community. The new concepts developed will provide new opportunities for European pharmaceutical industries.
Original text from CORDIS.
Participants
- UNIVERSITE LOUIS PASTEUR · STRASBOURGCoordinatorFrance
Links
Data: CORDIS, © European Union