Heroin Abuse Results in Shifted RNA Expression to Neurodegenerative Diseases and Attenuation of TNFα Signaling Pathway

Abstract

Repeated administration of heroin results in the induction of physical dependence, which is characterized as a behavioral state of compulsive drug seeking and a high rate of relapse even after periods of abstinence. However, few studies have been dedicated to characterization of the long-term alterations in heroin-dependent patients (HDPs). Herein, we examined the peripheral blood from 810 HDPs versus 500 healthy controls (HCs) according to the inclusion criteria. Compared with the control group, significant decreases of albumin, triglyceride, and total cholesterol levels were identified in HDPs (P < 0.001) versus HCs coupled with an insignificant decrease in BMI. Meanwhile, RNA-sequencing analyses were performed on blood of 16 long-term HDPs and 25 HCs. The results showed that the TNFα signaling pathway and hematopoiesis related genes were inhibited in HDPs. We further compared the transcriptome data to those of SCA2 and posttraumatic stress disorder patients, identified neurodegenerative diseases related genes were commonly up-regulated in coupled with biological processes “vesicle transport”, “mitochondria” and “splicing”. Genes in the categories of “protein ubiquitination” were down-regulated indicating potential biochemical alterations shared by all three comparative to their controls. In summary, this is a leading study performing a series of through investigations and using delicate approaches. Results from this study would benefit the study of drug addiction overall and link long-term heroin abuse to neurodegenerative diseases.

Quantitative Systems Pharmacological Analysis of Drugs of Abuse Reveals the Pleiotropy of Their Targets and the Effector Role of mTORC1

“…Notably, many of these pathways have been reported to play a role in mediating the effects of drugs of abuse. These include the top five [calcium signaling (Li et al, 2008 ), retrograde endocannabinoid signaling (Mechoulam and Parker, 2013 ), cGMP-PKG signaling (Shen et al, 2016 ), cAMP signaling (Philibin et al, 2011 ), and Rap1 signaling (Cahill et al, 2016 )] as well as some pathways with relatively low enrichment score (i.e., 0.2 < adjusted p-value), such as TNF signaling (Zhu et al, 2018 ), MAPK signaling (Sun et al, 2016 ), PI3K-Akt signaling (Neasta et al, 2011 ), NF-κB signaling (Nennig and Schank, 2017 ), and mTOR signaling (Neasta et al, 2014 ). We note that many receptors targeted by drugs of abuse take part in the KEGG neuroactive ligand-receptor interaction pathway.…”

Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder

“…Heroin users exhibit both transient and long-lasting cognitive impairments 56 – 58 , but it is currently unknown whether this is accompanied by striatal or cortical neurodegeneration. Intriguingly, a recent study reported neurodegenerative-like mRNA expression profiles in blood samples from over 800 heroin-dependent subjects 59 . Whether observed pTau pathology represents an early sign of vulnerability to neurodegenerative disorders later in life or reflects the lower end of the Tau-related spectrum of cognitive impairment is unknown.…”

Transcriptomic Analysis Reveals Receptor Subclass–Specific Immune Regulation of CD8+ T Cells by Opioids

“…The enhancement of cholesterol pathways in human CD8 + T cells by opioid exposure suggests that by regulating cholesterol metabolism, opioids may not only enhance their own signaling, they also modulate signal transduction from other lipid raft-associated receptors, including the TCR (46). Chronic opioid users have decreased serum triglyceride and cholesterol levels (36), suggesting that the cholesterol being synthesized may be integrated into the membrane rather than transported. Our results extend previous studies (42,43) by showing that opioids directly regulate the metabolic processes that contribute to their signal propagation.…”

“…Although to date no transcriptomic studies on immune responses of CD8 + T cells exposed to opioids have been reported, high throughput analysis in the CNS and mixed immune cell populations indicates that chronic opioid users have atypical protein coding and ncRNA transcriptional profiles (34)(35)(36). In this study, we investigate the early and cell type-specific transcriptomic regulation of CD8 + T cells by opioids and, to our knowledge, provide a first glimpse into the opioid-mediated control of key immune-related pathways, including lipid metabolism.…”