Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Opioid Receptors and Endorphinergic Systems 2.0

Special Issue Editors
Special Issue Information
Keywords
Published Papers

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

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 35324

Share This Special Issue

Special Issue Editor

Prof. Dr. Carlo Ventura

E-Mail Website
Guest Editor

Department of Medical and Surgical Sciences, School of Medicine, University of Bologna, Via G. Massarenti 9, 40138 Bologna, Italy
Interests: human mesenchymal stem cells; physical energies; regenerative medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Different cell populations express selected types of opioid receptors (i.e., m, d and k), being not only a target, but even a source for a number of biologically active end-products of endorphin genes, including for example the prodynorphin and the pro-enkephalin genes. The interaction between these peptides and their related receptors plays a crucial role in signal transduction circuitries. It is now increasingly becoming evident that the activity of endorphinergic systems is fashioned at multiple interconnected levels and it is controlled by a complex interplay between cell signaling, nucleosomal assembly, the establishment of multifaceted transcriptional motifs and the temporal and spatial organization of chromatin into loops and domains. Opioid peptides not only elicit paracrine and autocrine mechanisms of cell regulation, but they have also been found to act intracellularly. It turns out that cell nuclei harbor the potential for intrinsic signal transduction pathway(s). The term intracrine has been proposed for growth regulatory peptides that have been shown to act within their cell of synthesis at the level of the nuclear envelope, chromatin, or other subnuclear components. Consistent evidence links known intracrines with transcriptional responses and self-sustaining loops that behave as long-lived signals imparting features characteristic of cell growth, differentiation and memory. Within this context, we have shown that the prodynorphin gene and its biologically active product dynorphin B act as major conductors of cardiogenesis in both embryonic and adult stem cells, and that dynorphin B can act in an intracrine fashion at the level of nuclear opioid receptors in stem cells, coupling nuclear signaling with the transcription of cardiogenic genes.

Prof. Dr. Carlo Ventura
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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

opioid receptors
opioid peptides
autocrine
paracrine
intracrine regulation
cell signaling
gene expression
differentiation
growth regulation
somatic cells
stem cells

Published Papers (11 papers)

Download All Papers

Editorial

Jump to: Research, Review

4 pages, 195 KiB

Open AccessEditorial

Special Issue of International Journal of Molecular Sciences “Opioid Receptors and Endorphinergic Systems 2.0”

by Carlo Ventura

Int. J. Mol. Sci. 2021, 22(16), 8365; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168365 - 04 Aug 2021

Viewed by 1384

Abstract

Opioid peptides exhibit a wide-ranging tissue distribution and control multiple tissue functions not only through reflex mechanisms involving the central nervous system or the modulation of neurotransmitter release, but also by acting directly at the cellular level by targeting selected receptor subtypes (μ, [...] Read more.

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

Research

Jump to: Editorial, Review

20 pages, 1150 KiB

Open AccessArticle

Dysregulation of Nociceptin/Orphanin FQ and Dynorphin Systems in the Extended Amygdala of Alcohol Preferring Marchigian Sardinian (msP) Rats

by Francesca Felicia Caputi, Serena Stopponi, Laura Rullo, Martina Palmisano, Massimo Ubaldi, Sanzio Candeletti, Roberto Ciccocioppo and Patrizia Romualdi

Int. J. Mol. Sci. 2021, 22(5), 2448; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052448 - 28 Feb 2021

Cited by 11 | Viewed by 2397

Abstract

Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from negative moods and to relieve innate hypersensitivity to stress. This phenotype resembling a subset of alcohol use disorder (AUD) patients, appears to be linked to a dysregulation of the equilibrium between stress and antistress mechanisms in the extended amygdala. Here, comparing water and alcohol exposed msP and Wistar rats we evaluate the transcript expression of the anti-stress opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOP as well as of dynorphin (DYN) and its cognate κ-opioid receptor (KOP). In addition, we measured the transcript levels of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF1R), brain-derived neurotrophic factor (BDNF) and of the tropomyosin receptor kinase B receptor (Trk-B). Results showed an innately up-regulation of the CRFergic system, mediating negative mood and stress responses, as well as an inherent up-regulation of the anti-stress N/OFQ system, both in the amygdala (AMY) and bed nucleus of the stria terminalis (BNST) of msP rats. The up-regulation of this latter system may reflect an attempt to buffer the negative condition elicited by the hyperactivity of pro-stress mechanisms since results showed that voluntary alcohol consumption dampened N/OFQ. Alcohol exposure also reduced the expression of dynorphin and CRF transmissions in the AMY of msP rats. In the BNST, alcohol intake led to a more complex reorganization of these systems increasing receptor transcripts in msP rats, along with an increase of CRF and a decrease of N/OFQ transcripts, respectively. Moreover, mimicking the effects of alcohol in the AMY we observed that the activation of NOP receptor by intracerebroventricular administration of N/OFQ in msP rats caused an increase of BDNF and a decrease of CRF transcripts. Our study indicates that both stress and anti-stress mechanisms are dysregulated in the extended AMY of msP rats. The voluntary alcohol drinking, as well as NOP agonism, have a significant impact on neuropeptidergic systems arrangement, bringing the systems back to normalization. Full article

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

► Show Figures

Figure 1

13 pages, 2182 KiB

Open AccessArticle

κ-Opioid Signaling in the Lateral Hypothalamic Area Modulates Nicotine-Induced Negative Energy Balance

by Patricia Seoane-Collazo, Amparo Romero-Picó, Eva Rial-Pensado, Laura Liñares-Pose, Ánxela Estévez-Salguero, Johan Fernø, Rubén Nogueiras, Carlos Diéguez and Miguel López

Int. J. Mol. Sci. 2021, 22(4), 1515; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041515 - 03 Feb 2021

Cited by 10 | Viewed by 2064

Abstract

Several studies have reported that nicotine, the main bioactive component of tobacco, exerts a marked negative energy balance. Apart from its anorectic action, nicotine also modulates energy expenditure, by regulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. These effects are mainly controlled at the central level by modulation of hypothalamic neuropeptide systems and energy sensors, such as AMP-activated protein kinase (AMPK). In this study, we aimed to investigate the kappa opioid receptor (κOR)/dynorphin signaling in the modulation of nicotine’s effects on energy balance. We found that body weight loss after nicotine treatment is associated with a down-regulation of the κOR endogenous ligand dynorphin precursor and with a marked reduction in κOR signaling and the p70 S6 kinase/ribosomal protein S6 (S6K/rpS6) pathway in the lateral hypothalamic area (LHA). The inhibition of these pathways by nicotine was completely blunted in κOR deficient mice, after central pharmacological blockade of κOR, and in rodents where κOR was genetically knocked down specifically in the LHA. Moreover, κOR-mediated nicotine effects on body weight do not depend on orexin. These data unravel a new central regulatory pathway modulating nicotine’s effects on energy balance. Full article

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

► Show Figures

Figure 1

17 pages, 2060 KiB

Open AccessArticle

Altered mRNA Levels of Stress-Related Peptides in Mouse Hippocampus and Caudate-Putamen in Withdrawal after Long-Term Intermittent Exposure to Tobacco Smoke or Electronic Cigarette Vapour

by Lucia Carboni, Luisa Ponzoni, Daniela Braida, Mariaelvina Sala, Cecilia Gotti and Michele Zoli

Int. J. Mol. Sci. 2021, 22(2), 599; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020599 - 09 Jan 2021

Cited by 9 | Viewed by 2594

Abstract

Nicotine addiction is a severe public health problem. The aim of this study was to investigate the alterations in key neurotransmissions after 60 days of withdrawal from seven weeks of intermittent cigarette smoke, e-cigarette vapours, or an e-cigarette vehicle. In the nicotine withdrawal groups, increased depressive and anxiety/obsessive–compulsive-like behaviours were demonstrated in the tail suspension, sucrose preference and marble burying tests. Cognitive impairments were detected in the spatial object recognition test. A significant increase in Corticotropin-releasing factor (Crf) and Crf1 mRNA levels was observed, specifically after cigarette withdrawal in the caudate-putamen nucleus (CPu). The nociceptin precursor levels were reduced by cigarette (80%) and e-cigarette (50%) withdrawal in the CPu. The delta opioid receptor showed a significant reduction in the hippocampus driven by the exposure to an e-cigarette solubilisation vehicle, while the mRNA levels doubled in the CPu of mice that had been exposed to e-cigarettes. Withdrawal after exposure to e-cigarette vapour induced a 35% Bdnf mRNA decrease in the hippocampus, whereas Bdnf was augmented by 118% by cigarette withdrawal in the CPu. This study shows that long-term withdrawal-induced affective and cognitive symptoms associated to lasting molecular alterations in peptidergic signalling may determine the impaired neuroplasticity in the hippocampal and striatal circuitry. Full article

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

► Show Figures

Figure 1

14 pages, 1187 KiB

Open AccessArticle

Endogenous Opioid Signaling in the Mouse Retina Modulates Pupillary Light Reflex

by Allison M. Cleymaet, Casey-Tyler Berezin and Jozsef Vigh

Int. J. Mol. Sci. 2021, 22(2), 554; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020554 - 08 Jan 2021

Cited by 9 | Viewed by 2710

Abstract

Opioid peptides and their receptors are expressed in the mammalian retina; however, little is known about how they might affect visual processing. The melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), which mediate important non-image-forming visual processes such as the pupillary light reflex (PLR), express β-endorphin-preferring, µ-opioid receptors (MORs). The objective of the present study was to elucidate if opioids, endogenous or exogenous, modulate pupillary light reflex (PLR) via MORs expressed by ipRGCs. MOR-selective agonist [D-Ala², MePhe⁴, Gly-ol⁵]-enkephalin (DAMGO) or antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂ (CTAP) was administered via intravitreal injection. PLR was recorded in response to light stimuli of various intensities. DAMGO eliminated PLR evoked by light with intensities below melanopsin activation threshold but not that evoked by bright blue irradiance that activated melanopsin signaling, although in the latter case, DAMGO markedly slowed pupil constriction. CTAP or genetic ablation of MORs in ipRGCs slightly enhanced dim-light-evoked PLR but not that evoked by a bright blue stimulus. Our results suggest that endogenous opioid signaling in the retina contributes to the regulation of PLR. The slowing of bright light-evoked PLR by DAMGO is consistent with the observation that systemically applied opioids accumulate in the vitreous and that patients receiving chronic opioid treatment have slow PLR. Full article

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

► Show Figures

Figure 1

31 pages, 4608 KiB

Open AccessArticle

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

by Joanna Matalińska, Piotr F. J. Lipiński, Piotr Kosson, Katarzyna Kosińska and Aleksandra Misicka

Int. J. Mol. Sci. 2020, 21(20), 7738; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207738 - 19 Oct 2020

Cited by 8 | Viewed by 2296

Abstract

AA3266 is a hybrid compound consisting of opioid receptor agonist and neurokinin-1 receptor (NK1R) antagonist pharmacophores. It was designed with the desire to have an analgesic molecule with improved properties and auxiliary anticancer activity. Previously, the compound was found to exhibit high affinity for μ- and δ-opioid receptors, while moderate binding to NK1R. In the presented contribution, we report on a deeper investigation of this hybrid. In vivo, we have established that AA3266 has potent antinociceptive activity in acute pain model, comparable to that of morphine. Desirably, with prolonged administration, our hybrid induces less tolerance than morphine does. AA3266, contrary to morphine, does not cause development of constipation, which is one of the main undesirable effects of opioid use. In vitro, we have confirmed relatively strong cytotoxic activity on a few selected cancer cell lines, similar to or greater than that of a reference NK1R antagonist, aprepitant. Importantly, our compound affects normal cells to smaller extent what makes our compound more selective against cancer cells. In silico methods, including molecular docking, molecular dynamics simulations and fragment molecular orbital calculations, have been used to investigate the interactions of AA3266 with MOR and NK1R. Insights from these will guide structural optimization of opioid/antitachykinin hybrid compounds. Full article

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

► Show Figures

Figure 1

22 pages, 1816 KiB

Open AccessArticle

Glutathione and Glutathione-Like Sequences of Opioid and Aminergic Receptors Bind Ascorbic Acid, Adrenergic and Opioid Drugs Mediating Antioxidant Function: Relevance for Anesthesia and Abuse

by Robert Root-Bernstein, Beth Churchill and Miah Turke

Int. J. Mol. Sci. 2020, 21(17), 6230; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176230 - 28 Aug 2020

Cited by 8 | Viewed by 4169

Abstract

Opioids and their antagonists alter vitamin C metabolism. Morphine binds to glutathione (l-γ-glutamyl-l-cysteinyl-glycine), an intracellular ascorbic acid recycling molecule with a wide range of additional activities. The morphine metabolite morphinone reacts with glutathione to form a covalent adduct that is then excreted in urine. Morphine also binds to adrenergic and histaminergic receptors in their extracellular loop regions, enhancing aminergic agonist activity. The first and second extracellular loops of adrenergic and histaminergic receptors are, like glutathione, characterized by the presence of cysteines and/or methionines, and recycle ascorbic acid with similar efficiency. Conversely, adrenergic drugs bind to extracellular loops of opioid receptors, enhancing their activity. These observations suggest functional interactions among opioids and amines, their receptors, and glutathione. We therefore explored the relative binding affinities of ascorbic acid, dehydroascorbic acid, opioid and adrenergic compounds, as well as various control compounds, to glutathione and glutathione-like peptides derived from the extracellular loop regions of the human beta 2-adrenergic, dopamine D1, histamine H1, and mu opioid receptors, as well as controls. Some cysteine-containing peptides derived from these receptors do bind ascorbic acid and/or dehydroascorbic acid and the same peptides generally bind opioid compounds. Glutathione binds not only morphine but also naloxone, methadone, and methionine enkephalin. Some adrenergic drugs also bind to glutathione and glutathione-like receptor regions. These sets of interactions provide a novel basis for understanding some ways that adrenergic, opioid and antioxidant systems interact during anesthesia and drug abuse and may have utility for understanding drug interactions. Full article

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

► Show Figures

Graphical abstract

14 pages, 1410 KiB

Open AccessArticle

In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling

by Xiao Zhang, Shaurita D. Hutchins, Bruce E. Blough and Eric J. Vallender

Int. J. Mol. Sci. 2020, 21(11), 3999; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113999 - 03 Jun 2020

Cited by 5 | Viewed by 2254

Abstract

Interest has emerged in biased agonists at the mu opioid receptor (MOR) as a possible means for maintaining potent analgesis with reduced side effect profiles. While approaches measuring in vitro biased agonism are used in the development of these compounds, their therapeutic utility will ultimately be determined by in vivo functional effects. Nonhuman primates (NHPs) are the most translational model for evaluating the behavioral effects of candidate medications, but biased signaling of these drugs at NHP MOR receptors has been unstudied. The goal of the current work was to characterize MOR ligand bias in rhesus macaques, focusing on agonists that have previously been reported to show different patterns of biased agonism in rodents and humans. Downstream signaling pathways that responded to MOR activation were identified using a luciferase reporter array. Concentration-response curves for specific pathways (cAMP, NF-ĸB, MAPK/JNK) were generated using six agonists previously reported to differ in terms of signaling bias at rodent and human MORs. Using DAMGO as a reference ligand, relative cAMP, NF-ĸB and MAPK/JNK signaling by morphine, endomorphin-1, and TRV130 were found to be comparable between species. Further, the bias patterns of across ligands for NF-ĸB and MAPK/JNK were largely similar between species. There was a high degree of concordance between rhesus macaque and human MOR receptor signaling bias for all agonists tested, further demonstrating their utility for future translational behavioral studies. Full article

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

11 pages, 902 KiB

Open AccessReview

Tissue Regeneration: The Dark Side of Opioids

by Cécile Dromard Berthézène, Lise Rabiller, Géraldine Jourdan, Béatrice Cousin, Luc Pénicaud, Louis Casteilla and Anne Lorsignol

Int. J. Mol. Sci. 2021, 22(14), 7336; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147336 - 08 Jul 2021

Cited by 6 | Viewed by 4903

Abstract

Opioids are regarded as among the most effective analgesic drugs and their use for the management of pain is considered standard of care. Despite their systematic administration in the peri-operative period, their impact on tissue repair has been studied mainly in the context of scar healing and is only beginning to be documented in the context of true tissue regeneration. Indeed, in mammals, growing evidence shows that opioids direct tissue repair towards scar healing, with a loss of tissue function, instead of the regenerative process that allows for recovery of both the morphology and function of tissue. Here, we review recent studies that highlight how opioids may prevent a regenerative process by silencing nociceptive nerve activity and a powerful anti-inflammatory effect. These data open up new perspectives for inducing tissue regeneration and argue for opioid-restricted strategies for managing pain associated with tissue injury. Full article

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

► Show Figures

Figure 1

20 pages, 3039 KiB

Open AccessReview

Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants

by Anna Abrimian, Tamar Kraft and Ying-Xian Pan

Int. J. Mol. Sci. 2021, 22(7), 3779; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073779 - 06 Apr 2021

Cited by 13 | Viewed by 5703

Abstract

There exist three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin, all of which are derived from their precursors. These endogenous opioid peptides act through opioid receptors, including mu opioid receptor (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR), and play important roles not only in analgesia, but also many other biological processes such as reward, stress response, feeding and emotion. The MOR gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, generating multiple splice variants or isoforms. One type of these splice variants, the full-length 7 transmembrane (TM) Carboxyl (C)-terminal variants, has the same receptor structures but contains different intracellular C-terminal tails. The pharmacological functions of several endogenous opioid peptides through the mouse, rat and human OPRM1 7TM C-terminal variants have been considerably investigated together with various mu opioid ligands. The current review focuses on the studies of these endogenous opioid peptides and summarizes the results from early pharmacological studies, including receptor binding affinity and G protein activation, and recent studies of β-arrestin2 recruitment and biased signaling, aiming to provide new insights into the mechanisms and functions of endogenous opioid peptides, which are mediated through the OPRM1 7TM C-terminal splice variants. Full article

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

► Show Figures

Figure 1

13 pages, 312 KiB

Open AccessReview

Expression of Opioid Receptors in Cells of the Immune System

by Jana Brejchova, Vladimir Holan and Petr Svoboda

Int. J. Mol. Sci. 2021, 22(1), 315; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010315 - 30 Dec 2020

Cited by 27 | Viewed by 3985

Abstract

The observation of the immunomodulatory effects of opioid drugs opened the discussion about possible mechanisms of action and led researchers to consider the presence of opioid receptors (OR) in cells of the immune system. To date, numerous studies analyzing the expression of OR subtypes in animal and human immune cells have been performed. Some of them confirmed the expression of OR at both the mRNA and protein level, while others did not detect the receptor mRNA either. Although this topic remains controversial, further studies are constantly being published. The most recent articles suggested that the expression level of OR in human peripheral blood lymphocytes could help to evaluate the success of methadone maintenance therapy in former opioid addicts, or could serve as a biomarker for chronic pain diagnosis. However, the applicability of these findings to clinical practice needs to be verified by further investigations. Full article

(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)

Journal Menu

Journal Browser

Opioid Receptors and Endorphinergic Systems 2.0

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (11 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI