Description du sujet de thèse

Neuropathic pain affects 8% of the population and remains an unmet medical challenge. Chronic administration of opioids is prescribed for 40% of the patients despite the development of tolerance and risk of dependence. Mu opioid receptors mediate the analgesic and euphoric properties of opioids, but they also associate with delta opioid receptors to form heteromers. We observed increased mu-delta neuronal co-expression in the mouse brain in neuropathic condition and found that heteromerization of mu and delta opioid receptors alters mu receptor signalling and trafficking in primary neuronal cultures. However, due to the lack of selective ligands, distribution in the nervous system and functional role of mu-delta heteromers remain poorly characterized. Developing selective mu-delta tools would therefore significantly advance our knowledge on native mu-delta heteromers and help establishing their clinical relevance for treating neuropathic pain.
The PhD work aims to design novel chemical probes for selective detection of mu-delta opioid heteromers in mouse primary cultures and tissue of naïve and neuropathic mice. It relies on the expertise in design and chemical synthesis of pharmacological molecules of the Laboratory for Innovative Therapy (Dr Frederic Bihel, team Chemogenomics and Medicinal Chemistry, Faculty of Pharmacy, Illkirch) and the expertise in opioid receptor pharmacology and functional characterization of the team “Opioid, Nociception and Pain” (Dr Dominique Massotte, INCI).
Newly synthesized chemical probes will be pharmacologically characterized using native receptors (affinity and selectivity profiles, agonist or antagonist properties at G protein dependent and beta arrestin signaling). The ability of the probes to selectively target mu-delta opioid receptor heteromers will then be investigated by biochemical approaches and by immunodetection combined to high resolution fluorescence microscopy.

Contexte de travail

This project is supported by the MITI (Mission for Transverse and Interdisciplinary Initiatives) and the Centre National de la Recherche Scientifique (CNRS, https://www.cnrs.fr) . The CNRS is a leading research institute with worldwide recognition for its scientific excellence. The PhD work will be performed under the co-direction of Dr Dominique Massotte (INCI, Strasbourg, https://https://inci.neuro.unistra.fr/?page_id=10551&lang=en) and Dr Frederic Bihel (Faculty of Pharmacy, Illkirch, https://medchem.unistra.fr/). The institute of Cellular and Integrative Neuroscience (INCI) is a CNRS research laboratory with about 130 staff members has a strong partnership with the university of Strasbourg. Its mission is to explore the nervous system and its pathologies. The laboratory for Therapeutic Innovation (LIT) is affiliated to both the CNRS and the university of Strasbourg. It aims at designing, synthesizing and characterizing bioactive small molecular weight compounds. Research at LIT associates organic chemistry with a sound knowledge on biochemistry and pharmacology. The recruited PhD student (M/F) will therefore acquire a strong background in neurobiology and pharmacology with basic knowledge in peptide chemistry. Solid phase peptide synthesis, easily accessible to biologists, will be performed under Dr F Bihel's supervision. Dr D. Massotte will supervise the pharmacological and neurobiological validation of the ligands.
The PhD Student (M/F) will be registered at the doctoral school for Life and Health Sciences of Strasbourg university (https://ed.vie-sante.unistra.fr).

Contraintes et risques

Work dispatched between two laboratories
Chemical (e.g. CMR) and biological (primary cultures and cell lines) risks
Experimental work using mice