Abstract
Increasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double-fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization profile of mu and delta opioid receptors in primary hippocampal cultures. We established ligand selective mu–delta co-internalization upon activation by 1-[[4-(acetylamino)phenyl]methyl]-4-(2-phenylethyl)-4-piperidinecarboxylic acid, ethyl ester (CYM51010), [d-Ala2, NMe-Phe4, Gly-ol5]enkephalin (DAMGO), and deltorphin II, but not (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), morphine, or methadone. Co-internalization was driven by the delta opioid receptor, required an active conformation of both receptors, and led to sorting to the lysosomal compartment. Altogether, our data indicate that mu–delta co-expression, likely through heteromerization, alters the intracellular fate of the mu opioid receptor, which provides a way to fine-tune mu opioid receptor signaling. It also represents an interesting emerging concept for the development of novel therapeutic drugs and strategies.
Highlights
The opioid system modulates a large number of functions including nociception, emotional responses, reward and motivation, and cognition, as well as neuroendocrine physiology and autonomic functions [1,2]
/or mu-mCherry [11,13,26,27], both mu and delta opioid receptors were detected at the plasma membrane in primary hippocampal neurons under basal conditions (Figure 1A)
We examined whether other synthetic opioid agonists were able to promote mu–delta receptor co-internalization in primary hippocampal cultures
Summary
The opioid system modulates a large number of functions including nociception, emotional responses, reward and motivation, and cognition, as well as neuroendocrine physiology and autonomic functions [1,2]. It is composed of three G-protein-coupled receptors, mu, delta, and kappa, and three families of opioid peptides, the enkephalins, dynorphins, and endorphins [3]. Several decades of pharmacology have uncovered the complexity of the opioid pharmacology and evidenced functional interactions between receptors that can take place at different levels, including within the cell [4,5] This led to postulate the formation of functional association between different opioid receptor types to generate a novel entity with specific pharmacological, signaling, and trafficking properties called heteromers [6]. Mu and Molecules 2020, 25, 4493; doi:10.3390/molecules25194493 www.mdpi.com/journal/molecules
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