In vivo neuronal co-expression of mu and delta opioid receptors uncovers new therapeutic perspectives.
Opioid receptors belong to the G protein coupled receptor family. They modulate brain function at all levels of neural integration and therefore impact on autonomous, sensory, emotional and cognitive processing.In vivofunctional interaction between mu and delta opioid receptors are known to take place though it is still debated whether interactions occur at circuitry, cellular or molecular level. Also, the notion of receptor crosstalk via mu-delta heteromers is well documentedin vitrobutin vivoevidence remains scarce. To identify neurons in which receptor interactions could take place, we designed a unique double mutant knock-in mouse line that expresses functional red-fluorescent mu receptors and green-fluorescent delta receptors. We mapped mu and delta receptor distribution and co-localization throughout the nervous system and created the first interactive brain atlas with concomitant mu-delta visualization at subcellular resolution (http://mordor.ics-mci.fr/). Mu and delta receptors co-localize in neurons from subcortical networks but are mainly detected in separate neurons in the forebrain. Also, co-immunoprecipitation experiments indicated physical proximity in the hippocampus, a prerequisite to mu-delta heteromerization. Altogether, data suggest that mu-delta functional interactions take place at systems level for high-order emotional and cognitive processing whereas mu-delta may interact at cellular level in brain networks essential for survival, which has potential implications for innovative drug design in pain control, drug addiction and eating disorders.
Dept of Neurogenetics and Translational Medicine, IGBMC, F-67404 Illkirch, France.
Eric
E
Erbs
Dept of Neurogenetics and Translational Medicine, IGBMC, F-67404 Illkirch, France.
Lauren
L
Faget
Institut des Neurosciences Cellulaires et Intégratives, UPR 3212, F-67000 Strasbourg, France.
Pierre
P
Veinante
Dept of Neurogenetics and Translational Medicine, IGBMC, F-67404 Illkirch, France ; Douglas Research Centre, Dept Psychiatry, Faculty of Medicine, McGill University, H4H 1R3 Montréal, Canada.
Brigitte L
BL
Kieffer
Dept of Neurogenetics and Translational Medicine, IGBMC, F-67404 Illkirch, France ; Institut des Neurosciences Cellulaires et Intégratives, UPR 3212, F-67000 Strasbourg, France.
Dominique
D
Massotte