1Institut des Neurosciences Cellulaires et Intégratives, UPR 3212, Strasbourg, France
Opioid receptors are G protein coupled receptors that modulate brain function at all levels of neural integration, including autonomic, sensory, emotional and cognitive processing. Mu and delta opioid receptors functionally interact in vivo, but whether interactions occur at circuitry, cellular or molecular levels remains unsolved. To challenge the hypothesis of mu-delta heteromerization in the brain, we generated double knock-in mice co-expressing the mu opioid receptor fused to the red fluorescent protein mcherry and the delta opioid receptor fused to the green fluorescent protein eGFP. Dual receptor mapping throughout the nervous system revealed neuronal co-expression in dorsal root ganglia, spinal cord and within discrete brain areas (Erbs et al. (2015) Brain Struct Funct 220, 677). In the forebrain, mu and delta receptors were mainly detected in separate neurons, suggesting system-level interactions in high-order processing. In contrast, neuronal co-localization was detected in subcortical networks essential for survival involved in eating and sexual behaviors or perception and response to aversive stimuli. An opioid receptor atlas with concomitant mu-delta co-localization in the brain and spinal cord is accessible at http://mordor.ics-mci.fr/. In addition, physical close proximity between mu and delta receptors was detected by co-immunoprecipitation experiments strongly supporting the existence of in vivo mu-delta heteromers. Mu-delta physical association in neural networks associated with abnormal nociception, aversive aspects of drug withdrawal or eating disorders thus represents an attractive option for drug design and has initiated in-depth in vivo investigations to address the challenging issue of mu-delta heteromerization in physiology and disease.
This work is supported by FRM LPA20140129364