Liver Metabolomics and Inflammatory Profiles in Mouse Model of Fentanyl Overdose Treated with Beta-Lactams

Liver Metabolomics and Inflammatory Profiles in Mouse Model of Fentanyl Overdose Treated with Beta-Lactams

Fentanyl is a highly potent opioid analgesic that is approved medically to treat acute and chronic pain. There is a high potential for overdose-induced organ toxicities, including liver toxicity, and this might be due to the increase of recreational use of opioids. Several preclinical studies have d...

Full description

Saved in:
Bibliographic Details
Published in:Metabolites Vol. 13; no. 8; p. 965
Main Authors: Alasmari, Fawaz, Alasmari, Mohammed S, Assiri, Mohammed A, Alswayyed, Mohammed, Rizwan Ahamad, Syed, Alhumaydhi, Abdulrahman I, Arif, Bandar I, Aljumayi, Sahar R, AlAsmari, Abdullah F, Ali, Nemat, Childers, Wayne E, Abou-Gharbia, Magid, Sari, Youssef
Format: Journal Article
Language:English
Published: Basel MDPI AG 01-08-2023
MDPI
Subjects:
Alzheimer's disease
Amino acids
Amphetamines
Analgesics
Antibiotics
Beta lactam antibiotics
beta-lactams
Biomarkers
Brain
Carbohydrates
Ceftriaxone
Chromatography
Chronic pain
Dosage and administration
Drug abuse
Drug dosages
Drug overdose
Drugs
Ethanol
Fatty acids
Fentanyl
Gas chromatography
Gluconeogenesis
Glutamic acid transporter
Health aspects
Heroin
Inflammation
Interleukin 6
Ions
Lactose
Liver
Mass spectrometry
Mass spectroscopy
MC-100093
Metabolism
Metabolites
metabolomic
Metabolomics
Morphine
Narcotics
Opioids
Overdose
Pharmaceutical industry
Pharmacology, Experimental
Physiological aspects
Scientific imaging
Statistical analysis
Toxicity
β-Lactam antibiotics
Saudi Arabia
United States > US
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Fentanyl is a highly potent opioid analgesic that is approved medically to treat acute and chronic pain. There is a high potential for overdose-induced organ toxicities, including liver toxicity, and this might be due to the increase of recreational use of opioids. Several preclinical studies have demonstrated the efficacy of beta-lactams in modulating the expression of glutamate transporter-1 (GLT-1) in different body organs, including the liver. The upregulation of GLT-1 by beta-lactams is associated with the attenuation of hyperglutamatergic state, which is a characteristic feature of opioid use disorders. A novel experimental beta-lactam compound with no antimicrobial properties, MC-100093, has been developed to attenuate dysregulation of glutamate transport, in part by normalizing GLT-1 expression. A previous study showed that MC-100093 modulated hepatic GLT-1 expression with subsequent attenuation of alcohol-increased fat droplet content in the liver. In this study, we investigated the effects of fentanyl overdose on liver metabolites, and determined the effects of MC-100093 and ceftriaxone in the liver of a fentanyl overdose mouse model. Liver samples from control, fentanyl overdose, and fentanyl overdose ceftriaxone- or MC-100093-treated mice were analyzed for metabolomics using gas chromatography–mass spectrometry. Heatmap analysis revealed that both MC-100093 and ceftriaxone attenuated the effects of fentanyl overdose on several metabolites, and MC-100093 showed superior effects. Statistical analysis showed that MC-100093 reversed the effects of fentanyl overdose in some metabolites. Moreover, enrichment analysis revealed that the altered metabolites were strongly linked to the glucose-alanine cycle, the Warburg effect, gluconeogenesis, glutamate metabolism, lactose degradation, and ketone body metabolism. The changes in liver metabolites induced by fentanyl overdose were associated with liver inflammation, an effect attenuated with ceftriaxone pre-treatments. Ceftriaxone normalized fentanyl-overdose-induced changes in liver interleukin-6 and cytochrome CYP3A11 (mouse homolog of human CYP3A4) expression. Our data indicate that fentanyl overdose impaired liver metabolites, and MC-100093 restored certain metabolites.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:2218-1989
2218-1989
DOI:10.3390/metabo13080965