Archival ReportELK1 Transcription Factor Linked to Dysregulated Striatal Mu Opioid Receptor Signaling Network and OPRM1 Polymorphism in Human Heroin Abusers
Section snippets
Human Brain Specimens
Postmortem brain samples from heroin abusers and control subjects were collected at the Department of Forensic Medicine at Semmelweis University, Hungary, and the National Institute of Forensic Medicine at Karolinska Institutet, Stockholm, Sweden under the ethics guidelines approved by each institution. Heroin subjects died from heroin intoxication, were predominantly heroin users not receiving methadone or buprenorphine treatment, and were negative for human immunodeficiency virus infection.
Dysregulation of MOR Signaling Molecules in the Putamen of Human Heroin Abusers
Protein expression levels of MOR (89.55 ± 3.42%, p < .005; F2,43 = 6.73) and β-arrestin2 (87.11 ± 4.26%, p < .05; F3,41 = 8.1), which regulates MOR desensitization and internalization (43), were significantly reduced in heroin abusers compared with control subjects (Figure 1A,B), indicating that the tone of MOR signaling cascades may be altered. One of the key intracellular pathways activated upon MOR stimulation is the MAPK pathway, depicted in Figure 1C. We focused on the core components of
Discussion
The current study provides convergent lines of evidence identifying ELK1 disturbances in association with heroin use history and variants of the OPRM1 gene. The findings suggest that repeated activation of MOR, and subsequently the ERK pathway, efficiently controls the availability of ELK1 to regulate striatal transcriptional machinery in a dose-dependent manner. The ELK1 transcription factor has been generally overlooked in the context of addiction, but the current results implicate it as a
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2021, Current Research in NeurobiologyHeroin-based crack induces hyperalgesia through β-arrestin 2 redistribution and phosphorylation of Erk1/2 and JNK in the periaqueductal gray area
2019, Neuroscience LettersCitation Excerpt :Previous studies have also demonstrated that chronic administration of morphine into the PAG area produced tolerance and caused a significant increase in Erk1/2 phosphorylation [56,57]. It has also been shown that selective activation of Erk and JNK on descending pathways plays an important role in the ultra-low-dose morphine-induce hyperalgesia [58]. Melief et al. also showed that either gene knockout or inhibition of the JNK attenuated morphine-induced acute short-term tolerance in mice [59].
OPRD1 gene affects disease vulnerability and environmental stress in patients with heroin dependence in Han Chinese
2019, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :A genome-wide association study showed that minor C allele-carriers of rs1074287, located in the promoter region, have an increased risk for HD (Nielsen et al., 2008). Furthermore, intronic SNP rs2075572 was proposed to affect the expression of striatal ets-like kinase 1, suggesting that this variant could affect MOR-related striatal signaling (Sillivan et al., 2013). Despite the vast number of studies investigating the role of OPRM1 in HD, a consensus has not yet been reached on its functional consequences.