Morphine self-administration is inhibited by the antioxidant N‐acetylcysteine and the anti-inflammatory ibudilast; an effect enhanced by their co-administration

Journal
PLOS ONE
ISSN
1932-6203
Date Issued
2024
Author(s)
María Elena Quintanilla
Paola Morales
Daniela Santapau
Javiera Gallardo
Rocío Rebolledo
Gabriel Riveras
Tirso Acuña
Mario Herrera-Marschitz
Yedy Israel
Type
journal-article
DOI
URL
Abstract
<jats:sec id="sec001">
<jats:title>Background</jats:title>
<jats:p>The treatment of opioid addiction mainly involves the medical administration of methadone or other opioids, aimed at gradually reducing dependence and, consequently, the need for illicit opioid procurement. Thus, initiating opioid maintenance therapy with a lower level of dependence would be advantageous. There is compelling evidence indicating that opioids induce brain oxidative stress and associated glial activation, resulting in the dysregulation of glutamatergic homeostasis, which perpetuates drug intake. The present study aimed to determine whether inhibiting oxidative stress and/or neuroinflammation reduces morphine self-administration in an animal model of opioid dependence.</jats:p>
</jats:sec>
<jats:sec id="sec002">
<jats:title>Methods</jats:title>
<jats:p>Morphine dependence, assessed as voluntary morphine self-administration, was evaluated in Wistar-derived UChB rats. Following an extended period of morphine self-administration, animals were administered either the antioxidant N-acetylcysteine (NAC; 40 mg/kg/day), the anti-inflammatory ibudilast (7.5 mg/kg/day) or the combination of both agents. Oxidative stress and neuroinflammation were evaluated in the hippocampus, a region involved in drug recall that feeds into the nucleus accumbens, where the levels of the glutamate transporters GLT-1 and xCT were further assessed.</jats:p>
</jats:sec>
<jats:sec id="sec003">
<jats:title>Results</jats:title>
<jats:p>Daily administration of either NAC or ibudilast led to a mild reduction in voluntary morphine intake, while the co-administration of both therapeutic agents resulted in a marked inhibition (-57%) of morphine self-administration. The administration of NAC or ibudilast markedly reduced both the oxidative stress induced by chronic morphine intake and the activation of microglia and astrocytes in the hippocampus. However, only the combined administration of NAC + ibudilast was able to restore the normal levels of the glutamate transporter GLT-1 in the nucleus accumbens.</jats:p>
</jats:sec>
<jats:sec id="sec004">
<jats:title>Conclusion</jats:title>
<jats:p>Separate or joint administration of an antioxidant and anti-inflammatory agent reduced voluntary opioid intake, which could have translational value for the treatment of opioid use disorders, particularly in settings where the continued maintenance of oral opioids is a therapeutic option.</jats:p>
</jats:sec>
Project(s)
Subjects
acetylcysteine

; 

animals

; 

anti-inflammatory agents

; 

antioxidants

; 

excitatory amino acid transporter 2

; 

hippocampus

; 

indolizines

; 

male

; 

morphine

; 

morphine dependence

; 

nucleus accumbens

; 

oxidative stress

; 

pyrazoles

; 

pyridines

; 

rats

; 

rats, wistar

; 

self administration

; 

acepromazine

; 

acetylcysteine

; 

aldehyde dehydrogenase

; 

antibodies,antisera and immunoglobulins

; 

antiinflammatory agent

; 

antioxidant

; 

buffer

; 

cocaine

; 

distilled water

; 

dopamine

; 

glial fibrillary acidic protein

; 

glutathione

; 

glutathione reductase

; 

ibudilast

; 

ketamine

; 

macrogol

; 

malonaldehyde

; 

methadone

; 

morphine

; 

mu opiate receptor

; 

naloxone

; 

paracetamol

; 

paraformaldehyde

; 

sacubitril plus valsartan

; 

acetylcysteine

; 

antiinflammatory agent

; 

antioxidant

; 

excitatory amino acid transporter 2

; 

ibudilast

; 

indolizine derivative

; 

morphine

; 

pyrazole derivative

; 

pyridine derivative

; 

analysis of variance

; 

animal experiment

; 

animal model

; 

animal tissue

; 

article

; 

astrocyte

; 

chile

; 

controlled study

; 

diet supplementation

; 

drug self administration

; 

female

; 

hippocampus

; 

immunofluorescence

; 

immunohistochemistry

; 

immunoreactivity

; 

information processing

; 

kruskal wallis test

; 

lipid peroxidation

; 

microglia

; 

nervous system inflammation

; 

nonhuman

; 

normal distribution

; 

nucleus accumbens

; 

opiate addiction

; 

oxidative stress

; 

ph

; 

phagocytosis

; 

place preference

; 

post hoc analysis

; 

rat

; 

statistical analysis

; 

student t test

; 

upregulation

; 

animal

; 

drug effect

; 

drug therapy

; 

male

; 

metabolism

; 

morphine addiction

; 

oxidative stress

; 

wistar rat