A mu–delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks

Abstract

Opioid receptors are G protein-coupled receptors (GPCRs) that modulate brain function at all levels of neural integration, including autonomic, sensory, emotional and cognitive processing. Mu (MOR) and delta (DOR) opioid receptors functionally interact in vivo, but whether interactions occur at circuitry, cellular or molecular levels remains unsolved. To challenge the hypothesis of MOR/DOR heteromerization in the brain, we generated redMOR/greenDOR double knock-in mice and report dual receptor mapping throughout the nervous system. Data are organized as an interactive database offering an opioid receptor atlas with concomitant MOR/DOR visualization at subcellular resolution, accessible online. We also provide co-immunoprecipitation-based evidence for receptor heteromerization in these mice. In the forebrain, MOR and DOR are mainly detected in separate neurons, suggesting system-level interactions in high-order processing. In contrast, neuronal co-localization is detected in subcortical networks essential for survival involved in eating and sexual behaviors or perception and response to aversive stimuli. In addition, potential MOR/DOR intracellular interactions within the nociceptive pathway offer novel therapeutic perspectives.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-014-0717-9) contains supplementary material, which is available to authorized users.

Endogenous central amygdala mu-opioid receptor signaling promotes sodium appetite in mice

“…1B], whereas neither nor-BNI [KOR antagonist; main effect of treatment, F (1, 14) = 2.6, P = 0.131; Fig. 1C] nor naltrindole [DOR antagonist; main effect of treatment, F (1,14) = 0.5, P = 0.502; Fig. 1D] altered sodium intake.…”

“…The nonselective opioid receptor antagonist naltrexone reduced the cumulative amount of sodium consumed by sodium-depleted mice [main effect of treatment, F (1,14) = 75.3, P < 0.001; Fig. 1 A and F for normalized 120-min totals].…”

“…However, each opioid receptor subtype is broadly expressed throughout a multitude of brain regions (13,14), and therefore characterizing the precise opioidergic circuitries that contribute to sodium appetite is an important and ongoing focus of research. Studies in which exogenous opioid receptor agonists are infused into local regions of rat brain have proven informative and, for example, have demonstrated that increased MOR signaling within both the nucleus accumbens and ventral pallidum enhances the hedonic palatability of NaCl (15).…”

G Protein–Coupled Receptor Multimers: A Question Still Open Despite the Use of Novel Approaches

“…However, in a recent study, double knock-in mice expressing the MOR and d-opioid receptor (DOR) fused in frame to mCherry and enhanced green fluorescent protein (eGFP), respectively, showed colocalization of these receptors in the midbrain and hindbrain (Erbs et al, 2015). Coimmunoprecipitation using anti-mCherry and anti-eGFP antibodies revealed that MORmCherry and DOR-eGFP belong to the same complex in the hippocampus from these mice, which confirms earlier detection of these MOR-DOR complexes in this brain region using a heteromer-specific antibody (Gupta et al, 2010).…”

Impact des opiacés sur les neurones dopaminergiques

“…Sans en être le seul substrat, les systèmes dopaminergiques jouent un rôle important dans la dépendance aux opiacés et, depuis 1992 et les travaux fondateurs de Johnson et North [2], un modèle dit de désinhibition a été décrit afin d'expliquer ce recrutement des systèmes dopaminergiques mésencéphaliques. Dans ce modèle, les opiacés Vignette (Photo © Sébastien Granier).semblable entre les espèces de mammifères, il existe néanmoins quelques différences interspécifiques dans cette distribution ainsi que dans les niveaux d'expression entre les structures cérébrales [15][16][17][18]. Ces récepteurs sont toutefois présents, à des niveaux modérés, dans la VTA de tous les mammifères qui ont été étudiés.…”