Effect of human mesenchymal stem cell secretome administration on morphine self-administration and relapse in two animal models of opioid dependence

Quintanilla, Marı́a Elena; Quezada, Mauricio; Morales, Paola; Berríos-Cárcamo, Pablo; Santapau, Daniela; Ezquer, Marcelo; Herrera‐Marschitz, Mario; Israel, Yedy; Ezquer, Fernando

doi:10.1038/s41398-022-02225-0

Cited by 5 publications

(31 citation statements)

References 79 publications

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“…All statistical evaluations were conducted using GraphPad Prism model of voluntary morphine intake. 26 Building on this observation, we sought to determine whether the hMSC-derived secretome could also alleviate the withdrawal stage of opioid abuse.…”

Section: Discussionmentioning

confidence: 99%

“…This was performed immediately after intranasal delivery, with animals receiving a tail vein injection of 160 μL of secretome containing 25 μg of proteins derived from 1 × 10 6 preconditioned hMSCs. The control group received an equivalent volume of saline solution 26 …”

Section: Methodsmentioning

confidence: 99%

“…To evaluate oxidative stress in the hippocampus of rats subjected to morphine exposure, with or without hMSC‐derived secretome administrations and under control conditions (no morphine), we measured the ratio of oxidized glutathione normalized by total protein (GSSG/protein) and the level of a lipid peroxidation marker (malondialdehyde, MDA, levels). Both measurements serve as indicators of oxidative stress 26,58,60 . To evaluate the GSSG/protein ratio, we homogenized the hippocampus using a potassium buffer solution supplemented with 5 mM EDTA (pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, morphine activates a sensor of non‐endogenous molecules, the toll‐like receptor 4 (TLR4), promoting a pro‐inflammatory signaling cascade and upregulation of pro‐inflammatory cytokines 25 . The resulting neuroinflammation has been shown to be persistent, promoting the increase of brain oxidative stress 23,26,27 . An increase in neuroinflammation can alter behavior by modulating glutamatergic neurotransmission, first by upregulation of oxidant enzymes, and then by inactivation and downregulation of main glutamate transporters, like glutamate transporter‐1 (GLT‐1), in charge of glutamate uptake, and possibly the glutamate interchanger system X c − and its catalytic subunit xCT, that promotes the release of extrasynaptic glutamate 27–30 .…”

Section: Introductionmentioning

confidence: 99%

“…A reduction of these transporters levels and activity have been correlated to increased spillover of glutamate in the nucleus accumbens, increasing the activation of extrasynaptic glutamate receptors, in a model of heroin self‐administration and withdrawal 31 . Consequently, an increase in GLT‐1 levels in the hippocampus and nucleus accumbens is correlated with reduced morphine and heroin relapse and withdrawal 26,31,32 …”

Section: Introductionmentioning

confidence: 99%

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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

Quezada,

Ponce,

Berríos‐Cárcamo

et al. 2023

CNS Neurosci Ther

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BackgroundMorphine 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.MethodsTwo 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.ResultsIn 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.ConclusionData 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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%