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Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell-derived secretome in preclinical models of morphine dependence

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dc.contributor.authorEzquer, Marcelo
dc.contributor.authorGallardo, Javiera
dc.contributor.authorQuezada, Mauricio
dc.contributor.authorPonce, Carolina
dc.contributor.authorBerríos, Pablo
dc.contributor.authorSantapau, Daniela
dc.contributor.authorDe Gregorio, Cristian
dc.contributor.authorQuintanilla, María
dc.contributor.authorMorales, Paola
dc.contributor.authorHerreraz, Mario
dc.contributor.authorIsrael, Yedy
dc.contributor.authorAndrés, Paula
dc.contributor.authorHipólito, Lucia
dc.contributor.authorEzquer, Fernando
dc.date.accessioned2024-03-20T13:38:54Z
dc.date.available2024-03-20T13:38:54Z
dc.date.issued2023
dc.description.abstractBackground: 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. Methods: 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. Results: 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. Conclusion: 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.
dc.description.versionAceptada
dc.identifier.citationQuezada M, Ponce C, Berríos-Cárcamo P, Santapau D, Gallardo J, De Gregorio C, Quintanilla ME, Morales P, Ezquer M, Herrera-Marschitz M, Israel Y, Andrés-Herrera P, Hipólito L, Ezquer F. Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell-derived secretome in preclinical models of morphine dependence. CNS Neurosci Ther. 2023 Nov 6. doi: 10.1111/cns.14517
dc.identifier.doihttps://doi.org/10.1111/cns.14517
dc.identifier.urihttps://hdl.handle.net/11447/8553
dc.language.isoen
dc.subjectMesenchymal stem cells
dc.subjectNeuroinflammation
dc.subjectOpiod addiction
dc.subjectSecretome
dc.subjectWithdrawal
dc.titleAmelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell-derived secretome in preclinical models of morphine dependence
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceCNS neuroscience & therapeutics
dspace.entity.typePublication
relation.isAuthorOfPublication9cd4a8e6-6ba1-4344-80a2-45c260864d4c
relation.isAuthorOfPublication.latestForDiscovery9cd4a8e6-6ba1-4344-80a2-45c260864d4c

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