Opioid-specific brain connectivity dynamics distinguish analgesia from secondary effects: Studies in male mice
Abstract
The µ-opioid receptor (MOP) is a critical pharmaceutical target that mediates both the therapeutic benefits and adverse effects of opioid drugs. However, the large-scale neural circuit dynamics underlying key opioid effects, such as analgesia and respiratory depression, remain poorly understood, hindering the development of safer analgesics. Here, we present a multimodal experimental framework that integrates functional ultrasound imaging through the intact skull with behavioral and molecular analyses to investigate opioid-induced large-scale functional responses and their physiological relevance in awake, behaving male mice. Administration of major opioids—morphine, fentanyl, methadone, and buprenorphine—elicited robust, dose- and time-dependent reorganization of functional brain connectivity (FC) patterns, with magnitude scaling according to MOP agonist efficacy. This opioid-specific functional fingerprint is marked by decreased FC between the somatosensory cortex and hippocampal/thalamic regions and increased bilateral FC within the somatosensory cortex. Notably, this fingerprint was attenuated following tolerance induction and abolished by pharmacological or genetic MOP inactivation. Through power Doppler spectral analysis and lagged correlation measurements, we show that morphine perturbs temporal FC dynamics and the propagation of brain-wide oscillatory activity, disrupting critical-state dynamics. Importantly, we identify a dissociation between fast, transient processes—such as cerebral blood volume changes, locomotion, and respiratory depression—and slower processes driving FC reorganization, analgesia, and sustained MOP activation. This study provides mechanistic insights into opioid-induced network reorganization, establishes FC alterations as a reliable biomarker of opioid efficacy, and offers a framework for advancing the development of analgesic compounds with improved therapeutic windows and reduced side effects.
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BibTeX
@article{mariani2026opioidspecific,
title = {{Opioid-specific brain connectivity dynamics distinguish analgesia from secondary effects: Studies in male mice}},
author = {Jean-Charles Mariani and Samuel Le Meur-Diebolt and Laurianne Beynac and Renata Santos and Stefan Schulz and Thomas Deffieux and Mickael Tanter and Zsolt Lenkei and Andrea Kliewer},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = sep,
doi = {10.1073/pnas.2505464123},
url = {https://hal.science/hal-05728003v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Opioid-specific brain connectivity dynamics distinguish analgesia from secondary effects: Studies in male mice
AU - Jean-Charles Mariani
AU - Samuel Le Meur-Diebolt
AU - Laurianne Beynac
AU - Renata Santos
AU - Stefan Schulz
AU - Thomas Deffieux
AU - Mickael Tanter
AU - Zsolt Lenkei
AU - Andrea Kliewer
PY - 2026
DA - 2026/09/08
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2505464123
UR - https://hal.science/hal-05728003v1
AB - The µ-opioid receptor (MOP) is a critical pharmaceutical target that mediates both the therapeutic benefits and adverse effects of opioid drugs. However, the large-scale neural circuit dynamics underlying key opioid effects, such as analgesia and respiratory depression, remain poorly understood, hindering the development of safer analgesics. Here, we present a multimodal experimental framework that integrates functional ultrasound imaging through the intact skull with behavioral and molecular analyses to investigate opioid-induced large-scale functional responses and their physiological relevance in awake, behaving male mice. Administration of major opioids—morphine, fentanyl, methadone, and buprenorphine—elicited robust, dose- and time-dependent reorganization of functional brain connectivity (FC) patterns, with magnitude scaling according to MOP agonist efficacy. This opioid-specific functional fingerprint is marked by decreased FC between the somatosensory cortex and hippocampal/thalamic regions and increased bilateral FC within the somatosensory cortex. Notably, this fingerprint was attenuated following tolerance induction and abolished by pharmacological or genetic MOP inactivation. Through power Doppler spectral analysis and lagged correlation measurements, we show that morphine perturbs temporal FC dynamics and the propagation of brain-wide oscillatory activity, disrupting critical-state dynamics. Importantly, we identify a dissociation between fast, transient processes—such as cerebral blood volume changes, locomotion, and respiratory depression—and slower processes driving FC reorganization, analgesia, and sustained MOP activation. This study provides mechanistic insights into opioid-induced network reorganization, establishes FC alterations as a reliable biomarker of opioid efficacy, and offers a framework for advancing the development of analgesic compounds with improved therapeutic windows and reduced side effects.
SN - 0027-8424
SN - 1091-6490
ER -