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Mechanistic Effects of Human Variants Associated with Addiction

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 88825

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Special Issue Editor

Prof. Dr. Emil Alexov

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Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA
Interests: computational modeling of biological macromolecules; predicting molecular effects of disease-causing mutations; personalized medicine; macromolecular interactions; electrostatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Opioid medications are useful for treating acute pain; however, over the past two decades their use has been liberalized and their addictive potential underestimated, which has resulted in approximately 116 million people with opioid-prescription dependency. Opioid addiction comes in many forms, and it is a complex disease resulting from variants in multiple genes with relatively small effects, along with environmental and developmental factors. Thus, a genetic variant found in a given subset of an addicted population may not be found in an addicted population of a different background.

This Special Issue targets all aspects of opioid addiction, including factors as age, gender, race, and ethnicity, with a special emphasis on the genetic component contributing to addiction. Works reporting new variants associated with elevated opioid addiction risk are welcome. Investigations revealing mechanistical effects and the functional impact of these addiction-linked variants are particularly encouraged. Since opioid addiction is a complex disease, we are looking to receive papers addressing the impact of variants on the networks of interactions involving multiple genes.

Prof. Dr. Emil Alexov
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

opioid addiction
painkillers
complex disease
opioid use disorder
drug abuse
opioid dependence

Published Papers (5 papers)

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Research

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11 pages, 1014 KiB

Open AccessArticle

Opioid Addiction and Opioid Receptor Dimerization: Structural Modeling of the OPRD1 and OPRM1 Heterodimer and Its Signaling Pathways

by Bohua Wu, William Hand and Emil Alexov

Int. J. Mol. Sci. 2021, 22(19), 10290; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910290 - 24 Sep 2021

Cited by 4 | Viewed by 2658

Abstract

Opioid addiction is a complex phenomenon with genetic, social, and other components. Due to such complexity, it is difficult to interpret the outcome of clinical studies, and thus, mutations found in individuals with these addictions are still not indisputably classified as opioid addiction-causing variants. Here, we computationally investigated two such mutations, A6V and N40D, found in the mu opioid receptor gene OPRM1. The mutations are located in the extracellular domain of the corresponding protein, which is important to the hetero-dimerization of OPRM1 with the delta opioid receptor protein (OPRD1). The hetero-dimerization of OPRD1–OPRM1 affects the signaling pathways activated by opioids and natural peptides and, thus, could be considered a factor contributing to addiction. In this study, we built four 3D structures of molecular pathways, including the G-protein signaling pathway and the β-arrestin signaling pathway of the heterodimer of OPRD1–OPRM1. We also analyzed the effect of mutations of A6V and N40D on the stability of individual OPRM1/OPRD1 molecules and the OPRD1–OPRM1 heterodimer with the goal of inferring their plausible linkage with opioid addiction. It was found that both mutations slightly destabilize OPRM1/OPRD1 monomers and weaken their association. Since hetero-dimerization is a key step for signaling processes, it is anticipated that both mutations may be causing increased addiction risk. Full article

(This article belongs to the Special Issue Mechanistic Effects of Human Variants Associated with Addiction)

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Review

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11 pages, 611 KiB

Open AccessReview

Alcohol Addiction, Gut Microbiota, and Alcoholism Treatment: A Review

by Shao-Cheng Wang, Yuan-Chuan Chen, Shaw-Ji Chen, Chun-Hung Lee and Ching-Ming Cheng

Int. J. Mol. Sci. 2020, 21(17), 6413; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176413 - 03 Sep 2020

Cited by 66 | Viewed by 22857

Abstract

Alcohol addiction is a leading risk factor for personal death and disability. In 2016, alcohol use caused 2.2% of female deaths and 6.8% of male deaths, and disability-adjusted life years (DALYs) were 2.3% in female and 8.9% in male. Individuals with alcohol use disorder are at high risk of anxiety, depression, impaired cognition performance, and illicit drug use and are comorbid with liver disease, such as alcoholic hepatitis and liver cirrhosis, which is a major cause of personal death and disability worldwide. Psychological interventions, such as cognitive behavior therapy and motivational interviewing, as well as medical treatments, such as disulfiram, naltrexone, acamprosate, and nalmefene, are used for the treatment of alcohol addiction in Europe and the United States. However, the effect of current interventions is limited, and the need for additional interventions is substantial. Alcohol use impairs the intestinal barrier and causes changes to the intestinal permeability as well as the gut microbiota composition. Emerging studies have tried to reveal the role of the gut–brain axis among individuals with alcohol use disorder with or without alcohol liver disease. Bacterial products penetrate the impaired intestinal barrier and cause central inflammation; changes to the gut microbiota impair enterohepatic circulation of bile acids; alcohol abuse causes shortage of vital nutrients such as thiamine. Several studies have suggested that probiotics, through either oral administration or fecal microbiota transplantation, increased intestinal levels of potentially beneficial bacteria such as bifidobacteria and lactobacilli, improving the levels of liver-associated enzymes in patients with mild alcoholic hepatitis, and demonstrating beneficial psychotropic effects on anxiety and depression. In addition to medications for alcohol addiction, gene editing therapy such as clustered regularly interspaced short palindromic repeats (CRISPRs) may be another potential research target. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are associated with ADH and ALDH genes, are major enzymes involved in alcohol metabolism, and gene editing approaches may have the potential to directly modify specific genes to treat alcoholism caused by genetic defects. Further research is needed to study the effect of the combined treatment for alcohol addiction. Full article

(This article belongs to the Special Issue Mechanistic Effects of Human Variants Associated with Addiction)

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15 pages, 1600 KiB

Open AccessReview

Ankyrin Repeat and Kinase Domain Containing 1 Gene, and Addiction Vulnerability

by Alejandra Koeneke, Guillermo Ponce, Johanna Troya-Balseca, Tomás Palomo and Janet Hoenicka

Int. J. Mol. Sci. 2020, 21(7), 2516; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072516 - 04 Apr 2020

Cited by 14 | Viewed by 4117

Abstract

The TaqIA single nucleotide variant (SNV) has been tested for association with addictions in a huge number of studies. TaqIA is located in the ankyrin repeat and kinase domain containing 1 gene (ANKK1) that codes for a receptor interacting protein kinase. ANKK1 maps on the NTAD cluster along with the dopamine receptor D2 (DRD2), the tetratricopeptide repeat domain 12 (TTC12) and the neural cell adhesion molecule 1 (NCAM1) genes. The four genes have been associated with addictions, although TTC12 and ANKK1 showed the strongest associations. In silico and in vitro studies revealed that ANKK1 is functionally related to the dopaminergic system, in particular with DRD2. In antisocial alcoholism, epistasis between ANKK1 TaqIA and DRD2 C957T SNVs has been described. This clinical finding has been supported by the study of ANKK1 expression in peripheral blood mononuclear cells of alcoholic patients and controls. Regarding the ANKK1 protein, there is direct evidence of its location in adult and developing central nervous system. Together, these findings of the ANKK1 gene and its protein suggest that the TaqIA SNV is a marker of brain differences, both in structure and in dopaminergic function, that increase individual risk to addiction development. Full article

(This article belongs to the Special Issue Mechanistic Effects of Human Variants Associated with Addiction)

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23 pages, 10967 KiB

Open AccessReview

The Mechanisms Involved in Morphine Addiction: An Overview

by Joanna Listos, Małgorzata Łupina, Sylwia Talarek, Antonina Mazur, Jolanta Orzelska-Górka and Jolanta Kotlińska

Int. J. Mol. Sci. 2019, 20(17), 4302; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174302 - 03 Sep 2019

Cited by 96 | Viewed by 33533

Abstract

Opioid use disorder is classified as a chronic recurrent disease of the central nervous system (CNS) which leads to personality disorders, co-morbidities and premature death. It develops as a result of long-term administration of various abused substances, along with morphine. The pharmacological action of morphine is associated with its stimulation of opioid receptors. Opioid receptors are a group of G protein-coupled receptors and activation of these receptors by ligands induces significant molecular changes inside the cell, such as an inhibition of adenylate cyclase activity, activation of potassium channels and reductions of calcium conductance. Recent data indicate that other signalling pathways also may be involved in morphine activity. Among these are phospholipase C, mitogen-activated kinases (MAP kinases) or β-arrestin. The present review focuses on major mechanisms which currently are considered as essential in morphine activity and dependence and may be important for further studies. Full article

(This article belongs to the Special Issue Mechanistic Effects of Human Variants Associated with Addiction)

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17 pages, 709 KiB

Open AccessReview

Opioid Addiction, Genetic Susceptibility, and Medical Treatments: A Review

by Shao-Cheng Wang, Yuan-Chuan Chen, Chun-Hung Lee and Ching-Ming Cheng

Int. J. Mol. Sci. 2019, 20(17), 4294; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174294 - 02 Sep 2019

Cited by 63 | Viewed by 24785

Abstract

Opioid addiction is a chronic and complex disease characterized by relapse and remission. In the past decade, the opioid epidemic or opioid crisis in the United States has raised public awareness. Methadone, buprenorphine, and naloxone have proven their effectiveness in treating addicted individuals, and each of them has different effects on different opioid receptors. Classic and molecular genetic research has provided valuable information and revealed the possible mechanism of individual differences in vulnerability for opioid addiction. The polygenic risk score based on the results of a genome-wide association study (GWAS) may be a promising tool to evaluate the association between phenotypes and genetic markers across the entire genome. A novel gene editing approach, clustered, regularly-interspaced short palindromic repeats (CRISPR), has been widely used in basic research and potentially applied to human therapeutics such as mental illness; many applications against addiction based on CRISPR are currently under research, and some are successful in animal studies. In this article, we summarized the biological mechanisms of opioid addiction and medical treatments, and we reviewed articles about the genetics of opioid addiction, the promising approach to predict the risk of opioid addiction, and a novel gene editing approach. Further research on medical treatments based on individual vulnerability is needed. Full article

(This article belongs to the Special Issue Mechanistic Effects of Human Variants Associated with Addiction)

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