PT  - JOURNAL ARTICLE
AU  - Lyes Derouiche
AU  - Muzeyyen Ugur
AU  - Florian Pierre
AU  - Anika Mann
AU  - Stéphane Doridot
AU  - Stéphane Ory
AU  - Stefan Schulz
AU  - Dominique Massotte
TI  - Heteromerization of endogenous mu and delta opioid receptors tunes mu opioid receptor signaling and trafficking
AID  - 10.1101/455147
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 455147
4099  - http://biorxiv.org/content/early/2018/10/28/455147.short
4100  - http://biorxiv.org/content/early/2018/10/28/455147.full
AB  - 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 and in vivo. We established ligand selective mu-delta co-internalization upon activation by exogenous ligands and provide evidence for mu-delta co-internalization by the endogenous opioid peptide met-enkephalin, but not β-endorphin. Co-internalization was driven by the delta opioid receptor, required an active conformation of both receptors and led to sorting to the lysosomal compartment. This alteration in the mu opioid receptor intracellular fate was accompanied by sustained ERK1/2 phosphorylation. In addition, increased mu-delta neuronal co-localization in the rostral ventromedial medulla in a chronic neuropathic state suggests that mu-delta heteromers are involved in the regulation of nociceptive transmission