Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA–GABA transmission in highly addicted rats

Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 μg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder.

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Prolonged Withdrawal from Escalated Oxycodone is Associated with Increased Expression of Glutamate Receptors in the Rat Hippocampus

10.1101/2020.12.20.423680 ◽

2020 ◽

Author(s):

Aaron J Salisbury ◽

Christopher A Blackwood ◽

Jean Lud Cadet

Keyword(s):

Glutamate Receptors ◽

Molecular Mechanisms ◽

Quantitative Polymerase Chain Reaction ◽

Opioid Use Disorder ◽

Mrna Levels ◽

Opioid Use ◽

Self Administration ◽

Lever Pressing ◽

Polymerase Chain ◽

Long Access

People suffering from opioid use disorder (OUD) exhibit cognitive dysfunctions. Here, we investigated potential changes in the expression of glutamate receptors in rat hippocampi at 2 hours and 31 days after the last session of oxycodone self-administration (SA). RNA extracted from the hippocampus was used in quantitative polymerase chain reaction (qPCR) analyses. Rats, given long-access (9 hours per day) to oxycodone (LgA), took significantly more drug than rats exposed to short-access (3 hours per day) (ShA). In addition, LgA rats could be further divided into higher oxycodone taking (LgA-H) or lower oxycodone taking (LgA-L) groups, based on a cut-off of 50 infusions per day. LgA rats, but not ShA, rats exhibited incubation of oxycodone craving. In addition, LgA rats showed increased mRNA expression of GluA1-3 and GluN2a-c subunits as well as Grm3, Grm5, Grm6 and Grm8 subtypes of glutamate receptors after 31 days but not after 2 hours of stopping the SA experiment. Changes in GluA1-3, Grm6, and Grm8 mRNA levels also correlated with increased lever pressing (incubation) after long periods of withdrawal from oxycodone. More studies are needed to elucidate the molecular mechanisms involved in altering the expression of these receptors during withdrawal from oxycodone and/or incubation of drug seeking.

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Prolonged Withdrawal From Escalated Oxycodone Is Associated With Increased Expression of Glutamate Receptors in the Rat Hippocampus

Frontiers in Neuroscience ◽

10.3389/fnins.2020.617973 ◽

2021 ◽

Vol 14 ◽

Author(s):

Aaron J. Salisbury ◽

Christopher A. Blackwood ◽

Jean Lud Cadet

Keyword(s):

Glutamate Receptors ◽

Molecular Mechanisms ◽

Quantitative Polymerase Chain Reaction ◽

Opioid Use Disorder ◽

Mrna Levels ◽

Opioid Use ◽

Self Administration ◽

Lever Pressing ◽

Polymerase Chain ◽

Long Access

People suffering from opioid use disorder (OUD) exhibit cognitive dysfunctions. Here, we investigated potential changes in the expression of glutamate receptors in rat hippocampi at 2 h and 31 days after the last session of oxycodone self-administration (SA). RNA extracted from the hippocampus was used in quantitative polymerase chain reaction analyses. Rats, given long-access (9 h per day) to oxycodone (LgA), took significantly more drug than rats exposed to short-access (3 h per day) (ShA). In addition, LgA rats could be further divided into higher oxycodone taking (LgA-H) or lower oxycodone taking (LgA-L) groups, based on a cut-off of 50 infusions per day. LgA rats, but not ShA, rats exhibited incubation of oxycodone craving. In addition, LgA rats showed increased mRNA expression of GluA1-3 and GluN2a-c subunits as well as Grm3, Grm5, Grm6, and Grm8 subtypes of glutamate receptors after 31 days but not after 2 h of stopping the SA experiment. Changes in GluA1-3, Grm6, and Grm8 mRNA levels also correlated with increased lever pressing (incubation) after long periods of withdrawal from oxycodone. More studies are needed to elucidate the molecular mechanisms involved in altering the expression of these receptors during withdrawal from oxycodone and/or incubation of drug seeking.

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Vitamin D deficiency exacerbates UV/endorphin and opioid addiction

Science Advances ◽

10.1126/sciadv.abe4577 ◽

2021 ◽

Vol 7 (24) ◽

pp. eabe4577

Author(s):

Lajos V. Kemény ◽

Kathleen C. Robinson ◽

Andrea L. Hermann ◽

Deena M. Walker ◽

Susan Regan ◽

...

Keyword(s):

Vitamin D ◽

Opioid Use Disorder ◽

Opioid Addiction ◽

Opioid Use ◽

Endogenous Opioid ◽

Evolutionary Advantage ◽

Seeking Behavior ◽

Genetic And Environmental Factors ◽

Dose Dependent ◽

Genetic Mouse Models

The current opioid epidemic warrants a better understanding of genetic and environmental factors that contribute to opioid addiction. Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent association of VitD levels with self-reported opioid use. We used multiple pharmacologic approaches and genetic mouse models and found that deficiencies in VitD signaling amplify exogenous opioid responses that are normalized upon restoration of VitD signaling. Similarly, physiologic endogenous opioid analgesia and reward responses triggered by ultraviolet (UV) radiation are repressed by VitD signaling, suggesting that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin-seeking behavior until VitD levels are restored by cutaneous VitD synthesis. This feedback may carry the evolutionary advantage of maximizing VitD synthesis. However, unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior.

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Impact of opioids on oxidative status and related signaling pathways: An integrated view

Journal of Opioid Management ◽

10.5055/jom.2017.0392 ◽

2017 ◽

Vol 13 (4) ◽

pp. 241 ◽

Cited By ~ 4

Author(s):

Maryam Zahmatkesh, PhD ◽

Mehri Kadkhodaee, PharmD, PhD ◽

Ali Salarian, MD, PhD student ◽

Behjat Seifi, PhD ◽

Soheila Adeli, PhD

Keyword(s):

Redox Homeostasis ◽

Opioid Use Disorder ◽

Antioxidant Therapy ◽

In Vivo Studies ◽

Target Cells ◽

Enzymatic Antioxidants ◽

Opioid Use ◽

Pubmed Database

Background: Opioids produce reactive oxygen species (ROS) which are highly reactive molecules that damage cells and tissues, and are suggested to contribute to the opioid use disorders. Thus, antioxidant supplementation might improve the disturbance in redox (oxidation-reduction) homeostasis. However, randomized trials on antioxidant therapy have not shown beneficial effects.Objectives: The purpose of this review is to shed lights on the oxidative changes resulting from opioid use and to highlight the unanswered questions regarding oxidative profile in an effort to provide a comprehensive view of different aspects of an efficient antioxidant therapy in clinical settings.Methods: The studies were identified and gathered from the PubMed database over the past 16 years (2000-2016). Our search results were limited to articles in English, both animals and human and in vitro and in vivo studies. A total of 50 full text articles were reviewed and summarized.Results: Opioids elevate the level of ROS and decrease the function of enzymatic antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase. They increase the risk of vitamin deficiency and modify gene expression of target cells through ROS production. The effects of opioids on their target cells are exerted through different way and various mechanisms.Conclusion: Opioids modulate the redox homeostasis; therefore, understanding the profile of oxidative changes in individuals with opioid use disorder could be of significant benefits in the clinical setting, to help with selection of an efficient antioxidant therapy and diminishing oxidative damage.

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Orphanin FQ: Evidence for a Role in the Control of the Reproductive Neuroendocrine System

Endocrinology ◽

10.1210/en.2007-0011 ◽

2007 ◽

Vol 148 (10) ◽

pp. 4993-5001 ◽

Cited By ~ 25

Author(s):

Chad D. Foradori ◽

Marcel Amstalden ◽

Lique M. Coolen ◽

Sushma R. Singh ◽

Christine J. McManus ◽

...

Keyword(s):

Pulse Amplitude ◽

Pulse Frequency ◽

Brain Regions ◽

Orphanin Fq ◽

Endogenous Opioid ◽

Endogenous Opioid Peptide ◽

External Zone ◽

Gnrh Secretion

Orphanin FQ (OFQ), also known as nociceptin, is a member of the endogenous opioid peptide family that has been functionally implicated in the control of pain, anxiety, circadian rhythms, and neuroendocrine function. In the reproductive system, endogenous opioid peptides are involved in the steroid feedback control of GnRH pulses and the induction of the GnRH surge. The distribution of OFQ in the preoptic area and hypothalamus overlaps with GnRH, and in vitro evidence suggests that OFQ can inhibit GnRH secretion from hypothalamic fragments. Using the sheep as a model, we examined the potential anatomical colocalization between OFQ and GnRH using dual-label immunocytochemistry. Confocal microscopy revealed that approximately 93% of GnRH neurons, evenly distributed across brain regions, were also immunoreactive for OFQ. In addition, almost all GnRH fibers and terminals in the external zone of the median eminence, the site of neurosecretory release of GnRH, also colocalized OFQ. This high degree of colocalization suggested that OFQ might be functionally important in controlling reproductive endocrine events. We tested this possibility by examining the effects of intracerebroventricular administration of [Arg14, Lys15] OFQ, an agonist to the OFQ receptor, on pulsatile LH secretion. The agonist inhibited LH pulse frequency in both luteal phase and ovariectomized ewes and suppressed pulse amplitude in the latter. The results provide in vivo evidence supporting a role for OFQ in the control of GnRH secretion and raise the possibility that it acts as part of an ultrashort, autocrine feedback loop controlling GnRH pulses.

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Network-Based Discovery of Opioid Use Vulnerability in Rats Using the Bayesian Stochastic Block Model

10.1101/2021.06.30.450568 ◽

2021 ◽

Author(s):

Carter Allen ◽

Brittany N Kuhn ◽

Nazzareno Cannella ◽

Ayteria D Crow ◽

Analyse T Roberts ◽

...

Keyword(s):

Progressive Ratio ◽

Opioid Use Disorder ◽

Heroin Addiction ◽

Opioid Use ◽

Self Administration ◽

Block Model ◽

Similarity Network ◽

Stochastic Block Model ◽

Analysis Workflow ◽

Reinstatement Test

Opioid use disorder is a psychological condition that affects over 200,000 people per year in the U.S., causing the Centers for Disease Control and Prevention to label the crisis as a rapidly spreading public health epidemic. It has been found that the behavioral relationship between opioid exposure and development of opioid use disorder varies greatly between individuals, implying existence of sup-populations with varying degrees of opioid vulnerability. In this study, we assessed several behavioral variables across heroin taking, refraining and seeking to establish how these factors interact with one another resulting in a heroin dependent, resilient, or vulnerable behavioral phenotype. Over 400 (male and female) heterogeneous stock rats were used in these two studies, and data were collected from two geographically distinct locations. Rats underwent heroin self-administration training, followed by a progressive ratio and heroin-primed reinstatement test. Next, rats underwent extinction training and a cue-induced reinstatement test. To assess how these variables contribute to heroin addiction vulnerability, we developed a network-based data analysis workflow. Specifically, we integrated different cohorts of rats, remove possible batch effects, and constructed a rat-rat similarity network based on their behavioral patterns. We then implemented community detection on this similarity network using a Bayesian degree-corrected stochastic block model to uncover sub-populations of rats with differing levels of opioid vulnerability. We discovered three distinct behavioral sub-populations, each with significantly different behavioral outcomes that allowed for unique characterization of each cluster in terms of vulnerability to opioid use and seeking. We implement this analysis workflow as an open source R package, named mlsbm.

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Network-Based Discovery of Opioid Use Vulnerability in Rats Using the Bayesian Stochastic Block Model

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.745468 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carter Allen ◽

Brittany N. Kuhn ◽

Nazzareno Cannella ◽

Ayteria D. Crow ◽

Analyse T. Roberts ◽

...

Keyword(s):

Opioid Use Disorder ◽

Opioid Use ◽

Self Administration ◽

Block Model ◽

Linear Network ◽

Similarity Network ◽

Stochastic Block Model ◽

Behavioral Variables ◽

Analysis Workflow ◽

Reinstatement Test

Opioid use disorder is a psychological condition that affects over 200,000 people per year in the U.S., causing the Centers for Disease Control and Prevention to label the crisis as a rapidly spreading public health epidemic. The behavioral relationship between opioid exposure and development of opioid use disorder (OUD) varies greatly between individuals, implying existence of sup-populations with varying degrees of opioid vulnerability. However, effective pre-clinical identification of these sub-populations remains challenging due to the complex multivariate measurements employed in animal models of OUD. In this study, we propose a novel non-linear network-based data analysis workflow that employs seven behavioral traits to identify opioid use sub-populations and assesses contributions of behavioral variables to opioid vulnerability and resiliency. Through this analysis workflow we determined how behavioral variables across heroin taking, refraining and seeking interact with one another to identify potentially heroin resilient and vulnerable behavioral sub-populations. Data were collected from over 400 heterogeneous stock rats in two geographically distinct locations. Rats underwent heroin self-administration training, followed by a progressive ratio and heroin-primed reinstatement test. Next, rats underwent extinction training and a cue-induced reinstatement test. To enter the analysis workflow, we integrated data from different cohorts of rats and removed possible batch effects. We then constructed a rat-rat similarity network based on their behavioral patterns and implemented community detection on this similarity network using a Bayesian degree-corrected stochastic block model to uncover sub-populations of rats with differing levels of opioid vulnerability. We identified three statistically distinct clusters corresponding to distinct behavioral sub-populations, vulnerable, resilient and intermediate for heroin use, refraining and seeking. We implement this analysis workflow as an open source R package, named mlsbm.

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Biased signaling by endogenous opioid peptides

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2000712117 ◽

2020 ◽

Vol 117 (21) ◽

pp. 11820-11828 ◽

Cited By ~ 12

Author(s):

Ivone Gomes ◽

Salvador Sierra ◽

Lindsay Lueptow ◽

Achla Gupta ◽

Shawn Gouty ◽

...

Keyword(s):

Opioid Receptors ◽

Cultured Cells ◽

Opioid Use Disorder ◽

Receptor Activity ◽

Prolonged Treatment ◽

Opioid Use ◽

Endogenous Opioid System ◽

Endogenous Opioid ◽

Biased Signaling ◽

Brain Slice Preparation

Opioids, such as morphine and fentanyl, are widely used for the treatment of severe pain; however, prolonged treatment with these drugs leads to the development of tolerance and can lead to opioid use disorder. The “Opioid Epidemic” has generated a drive for a deeper understanding of the fundamental signaling mechanisms of opioid receptors. It is generally thought that the three types of opioid receptors (μ, δ, κ) are activated by endogenous peptides derived from three different precursors: Proopiomelanocortin, proenkephalin, and prodynorphin. Posttranslational processing of these precursors generates >20 peptides with opioid receptor activity, leading to a long-standing question of the significance of this repertoire of peptides. Here, we address some aspects of this question using a technical tour de force approach to systematically evaluate ligand binding and signaling properties ([35S]GTPγS binding and β-arrestin recruitment) of 22 peptides at each of the three opioid receptors. We show that nearly all tested peptides are able to activate the three opioid receptors, and many of them exhibit agonist-directed receptor signaling (functional selectivity). Our data also challenge the dogma that shorter forms of β-endorphin do not exhibit receptor activity; we show that they exhibit robust signaling in cultured cells and in an acute brain slice preparation. Collectively, this information lays the groundwork for improved understanding of the endogenous opioid system that will help in developing more effective treatments for pain and addiction.

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Drug-associated cues and drug dosage contribute to increased opioid seeking after abstinence

Scientific Reports ◽

10.1038/s41598-021-94214-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mary Tresa Zanda ◽

Gabriele Floris ◽

Stephanie E. Sillivan

Keyword(s):

Drug Dosage ◽

Opioid Use Disorder ◽

Drug Intake ◽

Opioid Use ◽

Self Administration ◽

Drug Seeking ◽

Drug Cues ◽

Rehabilitation Programs ◽

Key Factor ◽

Seeking Behavior

AbstractPatients with opioid use disorder experience high rates of relapse during recovery, despite successful completion of rehabilitation programs. A key factor contributing to this problem is the long-lasting nature of drug-seeking behavior associated with opioid use. We modeled this behavior in a rat drug self-administration paradigm in which drug-seeking is higher after extended abstinence than during the acute abstinence phase. The goal of this study was to determine the contribution of discrete or discriminative drug cues and drug dosage to time-dependent increases in drug-seeking. We examined heroin-seeking after 2 or 21 days of abstinence from two different self-administration cue-context environments using high or low doses of heroin and matched animals for their drug intake history. When lower dosages of heroin are used in discriminative or discrete cue protocols, drug intake history contributed to drug-seeking after abstinence, regardless of abstinence length. Incubation of opioid craving at higher dosages paired with discrete drug cues was not dependent on drug intake. Thus, interactions between drug cues and drug dosage uniquely determined conditions permissible for incubation of heroin craving. Understanding factors that contribute to long-lasting opioid-seeking can provide essential insight into environmental stimuli and drug-taking patterns that promote relapse after periods of successful abstinence.

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A VTA GABAergic neural circuit mediates visually evoked innate defensive responses

10.1101/493007 ◽

2018 ◽

Author(s):

Zheng Zhou ◽

Xuemei Liu ◽

Shanping Chen ◽

Zhijian Zhang ◽

Yu-anming Liu ◽

...

Keyword(s):

Visual Information ◽

Defensive Behavior ◽

Neural Circuit ◽

Flight Behavior ◽

Central Nucleus ◽

General Role ◽

Defensive Responses ◽

Electrophysiological Recordings

SUMMARYInnate defensive responses are essential for animal survival and are conserved across species. The ventral tegmental area (VTA) plays important roles in learned appetitive and aversive behaviors, but whether it plays a role in mediating or modulating innate defensive responses is currently unknown. We report that GABAergic neurons in the mouse VTA (VTAGABA+) are preferentially activated compared to VTA dopaminergic (VTADA+) neurons when a threatening visual stimulus evokes innate defensive behavior. Functional manipulation of these neurons showed that activation of VTAGABA+ neurons is indispensable for looming-evoked defensive flight behavior and photoactivation of these neurons is sufficient for looming-evoked defensive-like flight behavior, whereas no such role can be attributed for VTADA+ neurons. Viral tracing and in vivo and in vitro electrophysiological recordings showed that VTAGABA+ neurons receive direct excitatory inputs from the superior colliculus (SC). Furthermore, we showed that glutamatergic SC-VTA projections synapse onto VTAGABA+ neurons that project to the central nucleus of the amygdala (CeA) and that the CeA is involved in mediating the defensive behavior. Our findings demonstrate that visual information about aerial threats access to the VTAGABA+ neurons mediating innate behavioral responses, suggesting a more general role for the VTA.

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