Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell‐derived secretome in preclinical models of morphine dependence
Journal
CNS Neuroscience & Therapeutics
ISSN
1755-5930
1755-5949
Date Issued
2023
Author(s)
Mauricio Quezada
Carolina Ponce
Pablo Berríos‐Cárcamo
Daniela Santapau
Javiera Gallardo
María Elena Quintanilla
Paola Morales
Mario Herrera‐Marschitz
Yedy Israel
Paula Andrés‐Herrera
Lucia Hipólito
Type
Resource Types::text::journal::journal article
URL Institutional Repository
Abstract
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Morphine is an opiate commonly used in the treatment of moderate to severe pain. However, prolonged administration can lead to physical dependence and strong withdrawal symptoms upon cessation of morphine use. These symptoms can include anxiety, irritability, increased heart rate, and muscle cramps, which strongly promote morphine use relapse. The morphine‐induced increases in neuroinflammation, brain oxidative stress, and alteration of glutamate levels in the hippocampus and nucleus accumbens have been associated with morphine dependence and a higher severity of withdrawal symptoms. Due to its rich content in potent anti‐inflammatory and antioxidant factors, secretome derived from human mesenchymal stem cells (hMSCs) is proposed as a preclinical therapeutic tool for the treatment of this complex neurological condition associated with neuroinflammation and brain oxidative stress.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Two animal models of morphine dependence were used to evaluate the therapeutic efficacy of hMSC‐derived secretome in reducing morphine withdrawal signs. In the first model, rats were implanted subcutaneously with mini‐pumps which released morphine at a concentration of 10 mg/kg/day for seven days. Three days after pump implantation, animals were treated with a simultaneous intravenous and intranasal administration of hMSC‐derived secretome or vehicle, and withdrawal signs were precipitated on day seven by i.p. naloxone administration. In this model, brain alterations associated with withdrawal were also analyzed before withdrawal precipitation. In the second animal model, rats voluntarily consuming morphine for three weeks were intravenously and intranasally treated with hMSC‐derived secretome or vehicle, and withdrawal signs were induced by morphine deprivation.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In both animal models secretome administration induced a significant reduction of withdrawal signs, as shown by a reduction in a combined withdrawal score. Secretome administration also promoted a reduction in morphine‐induced neuroinflammation in the hippocampus and nucleus accumbens, while no changes were observed in extracellular glutamate levels in the nucleus accumbens.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Data presented from two animal models of morphine dependence suggest that administration of secretome derived from hMSCs reduces the development of opioid withdrawal signs, which correlates with a reduction in neuroinflammation in the hippocampus and nucleus accumbens.</jats:p></jats:sec>
Cite this document
Quezada, M., Ponce, C., Berríos‐Cárcamo, P., Santapau, D., Gallardo, J., De Gregorio, C., Quintanilla, M. E., Morales, P., Ezquer, M., Herrera‐Marschitz, M., Israel, Y., Andrés‐Herrera, P., Hipólito, L., & Ezquer, F. (2024). Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell‐derived secretome in preclinical models of morphine dependence. CNS Neuroscience & Therapeutics, 30(4), e14517. https://doi.org/10.1111/cns.14517
Subjects
mesenchymal stem cells
;
neuroinflammation
;
opiod addiction
;
secretome
;
withdrawal
;
administration, intranasal
;
animals
;
glutamates
;
humans
;
mesenchymal stem cells
;
morphine
;
morphine dependence
;
naloxone
;
narcotic antagonists
;
neuroinflammatory diseases
;
rats
;
secretome
;
substance withdrawal syndrome
;
glutamic acid derivative
;
malonaldehyde
;
morphine
;
morphine sulfate
;
naloxone
;
opiate
;
quinine
;
reactive oxygen metabolite
;
trichloroacetic acid
;
glutamic acid
;
morphine
;
naloxone
;
narcotic antagonist
;
adsc cell line
;
animal experiment
;
animal model
;
article
;
behavior
;
body mass
;
body weight
;
cell expansion
;
cell isolation
;
controlled study
;
drug exposure
;
drug use
;
drug withdrawal
;
forefoot
;
intranasal drug administration
;
intravenous drug administration
;
lipid peroxidation
;
lipid peroxidation assay
;
mastication
;
mesenchymal stem cell
;
mesenchymal stem cell derived secretome
;
microdialysis
;
morphine addiction
;
morphine withdrawal syndrome
;
nervous system inflammation
;
nonhuman
;
nucleus accumbens
;
oxidative stress
;
precipitation
;
program efficacy
;
rat
;
secretome
;
stretching
;
surgical technique
;
tremor
;
withdrawal syndrome
;
animal
;
human
;
morphine addiction
;
secretome
;
withdrawal syndrome