Metabolomic profiling of brain tissues of mice chronically exposed to heroin

Abstract

The chronic neurotoxicity of heroin on the nervous system is poorly understood. To address this issue, we comprehensively assessed the alteration of brain metabolomics caused by chronic heroin exposure and the withdrawal of heroin. Male C57BL/6J mice (n = 10) were given heroin (15 μmol/kg, i.p., twice a day) for 12 days while the withdrawal group received saline-treatment instead of heroin for the last two days. The control group received saline. We developed an UPLC-TOF/MS-based metabolomic approach to analyze the metabolites and carry out a metabolic pathway analysis in the brain. The major metabolites contributing to the discrimination were identified as amino acids, tricarboxylic-acid cycle intermediates, neurotransmitters, nucleotides and other compounds. A marked reduction in histidine and a slight but significant increase in phenylalanine and tryptophan were observed after heroin was withdrawn while the increased level of catecholamines was restored to baseline. Interestingly, N-acetylserotonin - a precursor of melatonin - was increased with the withdrawal of heroin while melatonin was markedly reduced along with the sub-chronic exposure to heroin. This shows that heroin disrupts not only the energy metabolism but also the biosynthesis of both catecholamines and melatonin in the mouse brain. Therefore, these substances are candidate biomarkers for chronic heroin-abuse.

Escalating morphine dosing in HIV-1 Tat transgenic mice with sustained Tat exposure reveals an allostatic shift in neuroinflammatory regulation accompanied by increased neuroprotective non-endocannabinoid lipid signaling molecules and amino acids

“…Specifically, it has been shown that immune activation can lead to diminished conversion of phenylalanine to tyrosine as evidenced by a higher phenylalanine/tyrosine (P/T) ratio [ 112 ], which has been shown to be present in HIV-infected patients [ 113 ] and potentially contributes to the dopamine deficiency in people living with HIV [ 114 ]. The downregulation of tyrosine in the spinal cord (but not striatum) following repeated morphine treatment supports findings in brain tissue of mice chronically exposed to heroin [ 60 ] and has been shown to allay some of the effects of opioid withdrawal [ 73 ]. In turn, we also report here that morphine leads to a significant upregulation of phenylalanine in the striatum (but not spinal cord) of Tat(−) mice.…”

“…In turn, we also report here that morphine leads to a significant upregulation of phenylalanine in the striatum (but not spinal cord) of Tat(−) mice. Similarly, rats self-administrating heroin [ 59 ] and mice undergoing heroin withdrawal [ 60 ] showed elevated levels of phenylalanine in serum. The lack of elevated phenylalanine concentrations in the spinal cord suggests regional differences in its metabolism (similar to tyrosine), which may coincide with regional differences in morphine concentration in the CNS [ 40 ].…”

“…Morphine-tolerant rodents show complex changes in eCB levels and/or related non-eCB lipid signaling molecules (e.g., N -oleoyl ethanolamide; OEA and N -palmitoyl ethanolamide; PEA), with reports ranging from upregulation to downregulation depending on the brain region, duration of exposure, and the particular eCB(s) or lipid(s) assessed [ 69 – 72 ]. Similarly, the levels of specific amino acids have been demonstrated to be altered in the brains of rodents exposed to opioids [ 59 , 60 ]. When given as dietary supplements, tyrosine, l -glutamine, and l -5-hydroxytryptophan allay some of the physical and emotional aspects of opioid withdrawal, presumably by restoring neurotransmitter levels to normative values [ 73 ].…”

Elevation of endocannabinoids in the brain by synthetic cannabinoid JWH-018: mechanism and effect on learning and memory

“…Currently, inferring specific health risks associated with the use of synthetic cannabinoids is challenging as limited toxic and pharmacological information is available, and the exact cellular mechanisms underlying memory and learning impairment elicited by substances such as JWH-018 are unclear. Metabolomics, the comprehensive study of global metabolites, is a highly sensitive and powerful tool for systemic toxicological approach 14,15 , and may provide comprehensive information on the dynamic changes induced by JWH-018. Therefore, we aimed to investigate the effects of JWH-018 on the hippocampal metabolome of mice to elucidate the potential mechanism of the impairment in learning and memory.…”

An Integrative Multi-Omics Workflow to Address Multifactorial Toxicology Experiments

“…Indeed, they have the potential to become a valuable tool when it comes to the exploration of new mechanisms of toxicity [5,6]. Proteins need a longer period to be either synthetized or degraded [7,8], while metabolomics can give a picture of both long-term and instantaneous reactions of the system induced by the stressor under study [9,10,11].…”