Mu Opioid Receptor-Expressing Neurons in the Dorsal Raphe Nucleus Are Involved in Reward Processing and Affective Behaviors.

Dorsal Raphe Nucleus Receptors, Opioid, mu Neurons / physiology Morphine / pharmacology Analgesics, Opioid Reward
Dorsal raphe nucleus Fiber photometry Mouse behavior Opioid circuitry Optogenetics Positive affect

Journal

Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264

Informations de publication

Date de publication:
01 12 2023
Historique:
received: 14 12 2022
revised: 12 05 2023
accepted: 24 05 2023
medline: 3 11 2023
pubmed: 8 6 2023
entrez: 7 6 2023
Statut: ppublish

Résumé

Mu opioid receptors (MORs) are key for reward processing, mostly studied in dopaminergic pathways. MORs are also expressed in the dorsal raphe nucleus (DRN), which is central for the modulation of reward and mood, but MOR function in the DRN remains underexplored. Here, we investigated whether MOR-expressing neurons of the DRN (DRN-MOR neurons) participate in reward and emotional responses. We characterized DRN-MOR neurons anatomically using immunohistochemistry and functionally using fiber photometry in responses to morphine and rewarding/aversive stimuli. We tested the effect of opioid uncaging on the DRN on place conditioning. We examined the effect of DRN-MOR neuron optostimulation on positive reinforcement and mood-related behaviors. We mapped their projections and selected DRN-MOR neurons projecting to the lateral hypothalamus for a similar optogenetic experimentation. DRN-MOR neurons form a heterogeneous neuronal population essentially composed of GABAergic (gamma-aminobutyric acidergic) and glutamatergic neurons. Calcium activity of DRN-MOR neurons was inhibited by rewarding stimuli and morphine. Local photo-uncaging of oxymorphone in the DRN produced conditioned place preference. DRN-MOR neuron optostimulation triggered real-time place preference and was self-administered, promoted social preference, and reduced anxiety and passive coping. Finally, specific optostimulation of DRN-MOR neurons projecting to the lateral hypothalamus recapitulated the reinforcing effects of total DRN-MOR neuron stimulation. Our data show that DRN-MOR neurons respond to rewarding stimuli and that their optoactivation has reinforcing effects and promotes positive emotional responses, an activity which is partially mediated by their projections to the lateral hypothalamus. Our study also suggests a complex regulation of DRN activity by MOR opioids, involving mixed inhibition/activation mechanisms that fine-tune DRN function.

Sections du résumé

BACKGROUND
Mu opioid receptors (MORs) are key for reward processing, mostly studied in dopaminergic pathways. MORs are also expressed in the dorsal raphe nucleus (DRN), which is central for the modulation of reward and mood, but MOR function in the DRN remains underexplored. Here, we investigated whether MOR-expressing neurons of the DRN (DRN-MOR neurons) participate in reward and emotional responses.
METHODS
We characterized DRN-MOR neurons anatomically using immunohistochemistry and functionally using fiber photometry in responses to morphine and rewarding/aversive stimuli. We tested the effect of opioid uncaging on the DRN on place conditioning. We examined the effect of DRN-MOR neuron optostimulation on positive reinforcement and mood-related behaviors. We mapped their projections and selected DRN-MOR neurons projecting to the lateral hypothalamus for a similar optogenetic experimentation.
RESULTS
DRN-MOR neurons form a heterogeneous neuronal population essentially composed of GABAergic (gamma-aminobutyric acidergic) and glutamatergic neurons. Calcium activity of DRN-MOR neurons was inhibited by rewarding stimuli and morphine. Local photo-uncaging of oxymorphone in the DRN produced conditioned place preference. DRN-MOR neuron optostimulation triggered real-time place preference and was self-administered, promoted social preference, and reduced anxiety and passive coping. Finally, specific optostimulation of DRN-MOR neurons projecting to the lateral hypothalamus recapitulated the reinforcing effects of total DRN-MOR neuron stimulation.
CONCLUSIONS
Our data show that DRN-MOR neurons respond to rewarding stimuli and that their optoactivation has reinforcing effects and promotes positive emotional responses, an activity which is partially mediated by their projections to the lateral hypothalamus. Our study also suggests a complex regulation of DRN activity by MOR opioids, involving mixed inhibition/activation mechanisms that fine-tune DRN function.

Identifiants

DOI: 10.1016/j.biopsych.2023.05.019 PMID: 37285896
pubmed: 37285896
pii: S0006-3223(23)01328-8
doi: 10.1016/j.biopsych.2023.05.019
pii:
doi:

Substances chimiques

Receptors, Opioid, mu 0
Morphine 76I7G6D29C
Analgesics, Opioid 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

842-851

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Auteurs

Lola Welsch (L)

Douglas Research Center, Department of Psychiatry, McGill University, Montréal, Quebec, Canada; INSERM U1114, Department of Psychiatry, University of Strasbourg, Strasbourg, France.

Esther Colantonio (E)

INSERM U1114, Department of Psychiatry, University of Strasbourg, Strasbourg, France.

Mathilde Frison (M)

Douglas Research Center, Department of Psychiatry, McGill University, Montréal, Quebec, Canada.

Desiree A Johnson (DA)

Neurobiology Department, School of the Biological Sciences, University of California San Diego, La Jolla, California.

Shannan P McClain (SP)

Neurobiology Department, School of the Biological Sciences, University of California San Diego, La Jolla, California.

Victor Mathis (V)

Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, UPR 3212, Strasbourg, France.

Matthew R Banghart (MR)

Neurobiology Department, School of the Biological Sciences, University of California San Diego, La Jolla, California.

Sami Ben Hamida (S)

Douglas Research Center, Department of Psychiatry, McGill University, Montréal, Quebec, Canada; INSERM UMR 1247, Université de Picardie Jules Verne, Amiens, France.

Emmanuel Darcq (E)

Douglas Research Center, Department of Psychiatry, McGill University, Montréal, Quebec, Canada; INSERM U1114, Department of Psychiatry, University of Strasbourg, Strasbourg, France.

Brigitte L Kieffer (BL)

Douglas Research Center, Department of Psychiatry, McGill University, Montréal, Quebec, Canada; INSERM U1114, Department of Psychiatry, University of Strasbourg, Strasbourg, France. Electronic address: brigitte.kieffer@unistra.fr.

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Classifications MeSH

questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Tronc cérébral › Mésencéphale › Pédoncule cérébral › Tegmentum du mésencéphale › Noyau dorsal du raphé › Mu Opioid Receptor-Expressing Neurons in the...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur aux neuropeptides › Récepteurs aux opioïdes › Récepteur mu › Mu Opioid Receptor-Expressing Neurons in the...
questionsmedicales.fr › Cellules › Neurones › Mu Opioid Receptor-Expressing Neurons in the...
questionsmedicales.fr › Composés polycycliques › Hydrocarbures aromatiques polycycliques › Phénanthrènes › Morphinanes › Dérivés de la morphine › Morphine › Mu Opioid Receptor-Expressing Neurons in the...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents du système nerveux central › Dépresseurs du système nerveux central › Stupéfiants › Analgésiques morphiniques › Mu Opioid Receptor-Expressing Neurons in the...
questionsmedicales.fr › Phénomènes psychologiques › Processus mentaux › Renforcement (psychologie) › Récompense › Mu Opioid Receptor-Expressing Neurons in the...