Chronic Morphine Leaves a Durable Fingerprint on Whole-Brain Functional Connectivity

Marion Sourty; Cédric Champagnol-Di Liberti; Md Taufiq Nasseef; Lola Welsch; Vincent Noblet; Emmanuel Darcq; Brigitte L Kieffer

doi:10.1016/j.biopsych.2023.12.007

Chronic Morphine Leaves a Durable Fingerprint on Whole-Brain Functional Connectivity

Biol Psychiatry. 2023 Dec 15:S0006-3223(23)01765-1. doi: 10.1016/j.biopsych.2023.12.007. Online ahead of print.

Authors

Marion Sourty¹, Cédric Champagnol-Di Liberti², Md Taufiq Nasseef³, Lola Welsch⁴, Vincent Noblet⁵, Emmanuel Darcq⁴, Brigitte L Kieffer⁶

Affiliations

¹ University of Strasbourg, French Institute of Health and Medical Research UMR-S 1329, Strasbourg Translational Neuroscience and Psychiatry, Centre de Recherche en Biomedicine de Strasbourg, Strasbourg, France; iCube, University of Strasbourg, National Centre for Scientific Research, Strasbourg, France.
² University of Strasbourg, French Institute of Health and Medical Research UMR-S 1329, Strasbourg Translational Neuroscience and Psychiatry, Centre de Recherche en Biomedicine de Strasbourg, Strasbourg, France.
³ Douglas Research Center, Department of Psychiatry, McGill University, Montréal, Quebec, Canada; Department of Mathematics, College of Science and Humanity Studies, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.
⁴ University of Strasbourg, French Institute of Health and Medical Research UMR-S 1329, Strasbourg Translational Neuroscience and Psychiatry, Centre de Recherche en Biomedicine de Strasbourg, Strasbourg, France; Douglas Research Center, Department of Psychiatry, McGill University, Montréal, Quebec, Canada.
⁵ iCube, University of Strasbourg, National Centre for Scientific Research, Strasbourg, France.
⁶ University of Strasbourg, French Institute of Health and Medical Research UMR-S 1329, Strasbourg Translational Neuroscience and Psychiatry, Centre de Recherche en Biomedicine de Strasbourg, Strasbourg, France; Douglas Research Center, Department of Psychiatry, McGill University, Montréal, Quebec, Canada. Electronic address: brigitte.kieffer@unistra.fr.

PMID: 38104648
DOI: 10.1016/j.biopsych.2023.12.007

Abstract

Background: Opioid use disorder is a chronic relapsing disorder. The brain adapts to opioids that are taken for pain treatment or recreational use so that abstinence becomes a true challenge for individuals with opioid use disorder. Studying brain dysfunction at this stage is difficult, and human neuroimaging has provided highly heterogeneous information.

Methods: Here, we took advantage of an established mouse model of morphine abstinence together with functional magnetic resonance imaging to investigate whole-brain functional connectivity (FC) first at rest and then in response to an acute morphine challenge during image acquisition.

Results: Hierarchical clustering of seed pair correlation coefficients showed modified FC in abstinent animals, brainwide and regardless of the condition. Seed-to-voxel analysis and random forest classification, performed on data at rest, indicated that the retrosplenial cortex (a core component of the default mode network) and the amygdala (a major aversion center) are the best markers of abstinence, thus validating the translatability of the study. Seed pair network clustering confirmed disruption of a retrosplenial cortex-centered network, reflecting major reorganization of brain FC. The latter analysis also identified a persistent but unreported morphine signature in abstinent mice at rest, which involves cortical and midbrain components and characterizes the enduring morphine footprint. Finally, dynamic FC analysis revealed that the intrascanner acute morphine challenge modified FC faster and more broadly in abstinent animals, demonstrating brainwide adaptations of FC reactivity to an acute opioid challenge.

Conclusions: This study used a unique experimental design to demonstrate that a prior history of chronic opioid exposure leaves a durable pharmacological signature on brain communication, with implications for pain management and recovery from opioid use disorder.

Keywords: Amygdala; Default mode network; Functional Magnetic Resonance Imaging; Mouse model; Opioid use disorder.