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Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures

Fentanyl is one of the most common opioid analgesics administered to patients undergoing surgery or for chronic pain management. While the side effects of chronic fentanyl abuse are recognized (e.g., addiction, tolerance, impairment of cognitive functions, and inhibit nociception, arousal, and respi...

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Autores principales: Lam, Doris, Sebastian, Aimy, Bogguri, Chandrakumar, Hum, Nicholas R., Ladd, Alexander, Cadena, Jose, Valdez, Carlos A., Fischer, Nicholas O., Loots, Gabriela G., Enright, Heather A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9403314/
https://www.ncbi.nlm.nih.gov/pubmed/36032789
http://dx.doi.org/10.3389/ftox.2022.983415
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author Lam, Doris
Sebastian, Aimy
Bogguri, Chandrakumar
Hum, Nicholas R.
Ladd, Alexander
Cadena, Jose
Valdez, Carlos A.
Fischer, Nicholas O.
Loots, Gabriela G.
Enright, Heather A.
author_facet Lam, Doris
Sebastian, Aimy
Bogguri, Chandrakumar
Hum, Nicholas R.
Ladd, Alexander
Cadena, Jose
Valdez, Carlos A.
Fischer, Nicholas O.
Loots, Gabriela G.
Enright, Heather A.
author_sort Lam, Doris
collection PubMed
description Fentanyl is one of the most common opioid analgesics administered to patients undergoing surgery or for chronic pain management. While the side effects of chronic fentanyl abuse are recognized (e.g., addiction, tolerance, impairment of cognitive functions, and inhibit nociception, arousal, and respiration), it remains poorly understood what and how changes in brain activity from chronic fentanyl use influences the respective behavioral outcome. Here, we examined the functional and molecular changes to cortical neural network activity following sub-chronic exposure to two fentanyl concentrations, a low (0.01 μM) and high (10 μM) dose. Primary rat co-cultures, containing cortical neurons, astrocytes, and oligodendrocyte precursor cells, were seeded in wells on either a 6-well multi-electrode array (MEA, for electrophysiology) or a 96-well tissue culture plate (for serial endpoint bulk RNA sequencing analysis). Once networks matured (at 28 days in vitro), co-cultures were treated with 0.01 or 10 μM of fentanyl for 4 days and monitored daily. Only high dose exposure to fentanyl resulted in a decline in features of spiking and bursting activity as early as 30 min post-exposure and sustained for 4 days in cultures. Transcriptomic analysis of the complex cultures after 4 days of fentanyl exposure revealed that both the low and high dose induced gene expression changes involved in synaptic transmission, inflammation, and organization of the extracellular matrix. Collectively, the findings of this in vitro study suggest that while neuroadaptive changes to neural network activity at a systems level was detected only at the high dose of fentanyl, transcriptomic changes were also detected at the low dose conditions, suggesting that fentanyl rapidly elicits changes in plasticity.
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spelling pubmed-94033142022-08-26 Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures Lam, Doris Sebastian, Aimy Bogguri, Chandrakumar Hum, Nicholas R. Ladd, Alexander Cadena, Jose Valdez, Carlos A. Fischer, Nicholas O. Loots, Gabriela G. Enright, Heather A. Front Toxicol Toxicology Fentanyl is one of the most common opioid analgesics administered to patients undergoing surgery or for chronic pain management. While the side effects of chronic fentanyl abuse are recognized (e.g., addiction, tolerance, impairment of cognitive functions, and inhibit nociception, arousal, and respiration), it remains poorly understood what and how changes in brain activity from chronic fentanyl use influences the respective behavioral outcome. Here, we examined the functional and molecular changes to cortical neural network activity following sub-chronic exposure to two fentanyl concentrations, a low (0.01 μM) and high (10 μM) dose. Primary rat co-cultures, containing cortical neurons, astrocytes, and oligodendrocyte precursor cells, were seeded in wells on either a 6-well multi-electrode array (MEA, for electrophysiology) or a 96-well tissue culture plate (for serial endpoint bulk RNA sequencing analysis). Once networks matured (at 28 days in vitro), co-cultures were treated with 0.01 or 10 μM of fentanyl for 4 days and monitored daily. Only high dose exposure to fentanyl resulted in a decline in features of spiking and bursting activity as early as 30 min post-exposure and sustained for 4 days in cultures. Transcriptomic analysis of the complex cultures after 4 days of fentanyl exposure revealed that both the low and high dose induced gene expression changes involved in synaptic transmission, inflammation, and organization of the extracellular matrix. Collectively, the findings of this in vitro study suggest that while neuroadaptive changes to neural network activity at a systems level was detected only at the high dose of fentanyl, transcriptomic changes were also detected at the low dose conditions, suggesting that fentanyl rapidly elicits changes in plasticity. Frontiers Media S.A. 2022-08-11 /pmc/articles/PMC9403314/ /pubmed/36032789 http://dx.doi.org/10.3389/ftox.2022.983415 Text en Copyright © 2022 Lam, Sebastian, Bogguri, Hum, Ladd, Cadena, Valdez, Fischer, Loots and Enright. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Toxicology
Lam, Doris
Sebastian, Aimy
Bogguri, Chandrakumar
Hum, Nicholas R.
Ladd, Alexander
Cadena, Jose
Valdez, Carlos A.
Fischer, Nicholas O.
Loots, Gabriela G.
Enright, Heather A.
Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures
title Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures
title_full Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures
title_fullStr Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures
title_full_unstemmed Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures
title_short Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures
title_sort dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures
topic Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9403314/
https://www.ncbi.nlm.nih.gov/pubmed/36032789
http://dx.doi.org/10.3389/ftox.2022.983415
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