Molecular and functional characterization of novel communication pathways based on pronociceptin-derived peptides and their receptors in the nervous system

Información del proyecto

Identificador del acuerdo de subvención: BMH4972317

Proyecto cerrado

Fecha de inicio 1 Octubre 1997

Fecha de finalización 30 Septiembre 2000

Financiado con arreglo a

• Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Coste total

Sin datos

Aportación de la UE

Sin datos

Coordinado por

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
France

Objetivo

To determine experimentally and in silico, as a prerequisite to a rational medicinal chemistry, three-dimensional models of the nociceptin-ORL1 receptor complex.-
To identify and subsequently clone, as potential novel targets for therapeutic agents, specific receptors to pronociceptin-derived (orphan) neuropeptides.
To firmly establish that nociceptin and pronociceptin-derived (orphan) peptides regulate nociception, and identify other functions of pathological interest.

The objectives of the project are to provide a detailed molecular and functional description of novel peptide-based communication pathways that are thought to modulate pain in the nervous system. One pathway makes use of nociceptin, the recently identified natural agonist of ORL1, a Gprotein-coupled neuroreceptor closely related to opioid receptors. The other may utilize F15Q, a peptide of yet unknown receptor, which is also present as one potentially excisable copy in pronociceptin, nociceptin's precursorpolypeptide. When centrally (i.c.v.) administered in rnice, nociceptin and F15Qboth render the animals' hyperreactive to thermal nociceptive stimulation, suggesting that the two heptadecapeptides may normally act to produce orexacerbate the pain sensation. Most irnportantly then, antagonists of thenociceptin (ORL1) and/or F15Q (unknown) receptors should display analgesic activity. Molecular description: in order to provide a structural basis to the rational design of better adapted ligands, including antagonists (potential new analgesics), the functional architecture of the ORLI receptor and the structure-activity relationships of nociceptin (Noc) will be analysed by means of protein engineering (receptor) and peptide synthesis (ligand). 3-D models of the Noc-ORLl receptor complex will provide assistance. In parallel, a specific receptor for the F15Q "orphan" peptide will be searched for as a specific, high affinity [3HlF15Q binding site in nerve tissue. If the site proves to exist, we propose to clone the cDNA encoding the F15Q receptor.

Functional description: localization of pronociceptin's mRNA and/or of the peptides (nociceptin and F15Q) along pain pathways in the rat and/or mouse nervous system will provide additional although indirect evidence that the pronociceptin gene products are involved in nociperception. More directly the two peptides will be tested for pro-nociceptive (and other) activities in vivo, using behavioural paradigms based on various pain modalities (thermal vs. mechanical, cutaneous vs. visceral, spinal vs. supraspinal, acute vs. chronic) and electrophysiological studies will be carried out to demonstrate direct (spinal) or indirect (supraspinal) stimulatory effects of nociceptin and/orF15Q on spinal nociceptive neurons in situ. It is also envisaged to generate transgenic mouse strains, which do not express a functional ORLl orpronociceptin gene, hence, which might display reduced pain sensitivity. Along this same line, we propose to search for mutations of the ORLl and pronociceptin genes in blood samples from patients suffering congenital insensitivity to pain. This multidisciplinary approach involving five research teams with complementary technological abilities should speed up comprehension of the physiological roles of pronociceptin-derived neuropeptides and, most importantly, provide the pharmaceutical industry with new targets and the tools to develop novel, non-opiate analgesics. 07

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › neurobiología
• ciencias médicas y de la salud › medicina básica › química medicinal
• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias naturales › ciencias biológicas › genética › mutación

Programa(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Tema(s)

• 3.7 - Pain regulation and relief

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

CSC - Cost-sharing contracts

Coordinador

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE

• Aportación de la UE: Sin datos
• Dirección: 205,Route de Narbonne 205 ; 31077 TOULOUSE ; Francia
• Coste total: Sin datos

Participantes (3)

UNIVERSITE LIBRE DE BRUXELLES

Bélgica

• Aportación de la UE: Sin datos
• Dirección: 808,Route de Lennik 808 Campus Erasme - Building C ; 1070 BRUXELLES
• Coste total: Sin datos

University College London

Reino Unido

• Aportación de la UE: Sin datos
• Dirección: Rayne Institute Gower Street ; WC1E 6BT London
• Coste total: Sin datos

Université de Rouen - Haute Normandie

Francia

• Aportación de la UE: Sin datos
• Dirección: Avenue de l'Université ; 76803 Saint-Etienne-du-Rouvray
• Coste total: Sin datos