scholarly journals Vitamin D deficiency exacerbates UV/endorphin and opioid addiction

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.

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

2020 ◽  
Vol 117 (4) ◽  
pp. 2140-2148 ◽  
Author(s):  
Marsida Kallupi ◽  
Lieselot L. G. Carrette ◽  
Jenni Kononoff ◽  
Leah C. Solberg Woods ◽  
Abraham A. Palmer ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Opioid Use Disorder ◽  
Central Nucleus ◽  
Orphanin Fq ◽  
Opioid Use ◽  
Self Administration ◽  
Endogenous Opioid ◽  
Electrophysiological Recordings ◽  
Gaba Transmission

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.

scholarly journals Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid dependence

2021 ◽  
Author(s):  
Olivia Corradin ◽  
Richard Sallari ◽  
An T. Hoang ◽  
Bibi S Kassim ◽  
Gabriella Ben Hutta ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Opioid Dependence ◽  
Opioid Use Disorder ◽  
Opioid Overdose ◽  
Opioid Use ◽  
Prefrontal Cortical ◽  
Patient Heterogeneity ◽  
Dorsolateral Prefrontal ◽  
Number Of Sexual Partners ◽  
Genetic And Environmental Factors

Opioid dependence is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. We interrogated the effects of opioid dependence on the brain using ChIP-seq to quantify patterns of H3K27 acetylation in dorsolateral prefrontal cortical neurons isolated from 51 opioid-overdose cases and 51 accidental death controls. Among opioid cases, we observed global hypoacetylation and identified 388 putative enhancers consistently depleted for H3K27ac. Machine learning on H3K27ac patterns predicts case-control status with high accuracy. We focus on case-specific regulatory alterations, revealing 81,399 hypoacetylation events, uncovering vast inter-patient heterogeneity. We developed a strategy to decode this heterogeneity based on convergence analysis, which leveraged promoter-capture Hi-C to identify five genes over-burdened by alterations in their regulatory network or "plexus": ASTN2, KCNMA1, DUSP4, GABBR2, ENOX1. These convergent loci are enriched for opioid use disorder risk genes and heritability for generalized anxiety, number of sexual partners, and years of education. Overall, our multi-pronged approach uncovers neurobiological aspects of opioid dependence and captures genetic and environmental factors perpetuating the opioid epidemic.

scholarly journals Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1900 ◽  
Author(s):  
Joshua K. Hakimian ◽  
Tien S. Dong ◽  
Jorge A. Barahona ◽  
Venu Lagishetty ◽  
Suchi Tiwari ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Opioid Dependence ◽  
Opioid Addiction ◽  
Omega 3 ◽  
Opioid Use ◽  
Dietary Interventions ◽  
Pufa Supplementation ◽  
Microbiome Composition ◽  
Seeking Behavior

Opioids are highly addictive substances with a relapse rate of over 90%. While preclinical models of chronic opioid exposure exist for studying opioid dependence, none recapitulate the relapses observed in human opioid addiction. The mechanisms associated with opioid dependence, the accompanying withdrawal symptoms, and the relapses that are often observed months or years after opioid dependence are poorly understood. Therefore, we developed a novel model of chronic opioid exposure whereby the level of administration is self-directed with periods of behavior acquisition, maintenance, and then extinction alternating with reinstatement. This profile arguably mirrors that seen in humans, with initial opioid use followed by alternating periods of abstinence and relapse. Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 polyunsaturated fatty acids (n-3 PUFAs), may reduce substance misuse liability. Using the self-directed intake model, we characterize the observed profile of opioid use and demonstrate that an n-3-PUFA-enriched diet ameliorates oxycodone-seeking behaviors in the absence of drug availability and reduces anxiety. Guided by the major role gut microbiota have on brain function, neuropathology, and anxiety, we profile the microbiome composition and the effects of chronic opioid exposure and n-3 PUFA supplementation. We demonstrate that the withdrawal of opioids led to a significant depletion in specific microbiota genera, whereas n-3 PUFA supplementation increased microbial richness, phylogenetic diversity, and evenness. Lastly, we examined the activation state of microglia in the striatum and found that n-3 PUFA supplementation reduced the basal activation state of microglia. These preclinical data suggest that a diet enriched in n-3 PUFAs could be used as a treatment to alleviate anxiety induced opioid-seeking behavior and relapse in human opioid addiction.

scholarly journals Biased signaling by endogenous opioid peptides

2020 ◽  
Vol 117 (21) ◽  
pp. 11820-11828 ◽  
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.

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

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.

scholarly journals The Genomics of Opioid Addiction Longitudinal Study (GOALS): study design for a prospective evaluation of genetic and non-genetic factors for development of and recovery from opioid use disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jessica Heil ◽  
Stefan Zajic ◽  
Emily Albertson ◽  
Andrew Brangan ◽  
Iris Jones ◽  
...  
Keyword(s):  
Risk Factors ◽  
Longitudinal Study ◽  
Treatment Outcomes ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
The United States ◽  
Opioid Use Disorder ◽  
Opioid Addiction ◽  
Complex Data ◽  
Opioid Use

Abstract Background The opioid use disorder and overdose crisis in the United States affects public health as well as social and economic welfare. While several genetic and non-genetic risk factors for opioid use disorder have been identified, many of the genetic associations have not been independently replicated, and it is not well understood how these factors interact. This study is designed to evaluate relationships among these factors prospectively to develop future interventions to help prevent or treat opioid use disorder. Methods The Genomics of Opioid Addiction Longitudinal Study (GOALS) is a prospective observational study assessing the interplay of genetic and non-genetic by collecting comprehensive genetic and non-genetic information on 400 participants receiving medication for opioid use disorder. Participants will be assessed at four time points over 1 year. A saliva sample will be collected for large-scale genetic data analyses. Non-genetic assessments include validated surveys measuring addiction severity, depression, anxiety, and adverse childhood experiences, as well as treatment outcomes such as urine toxicology results, visit frequency, and number of pre and post-treatment overdoses extracted from electronic medical records. Discussion We will use these complex data to investigate the relative contributions of genetic and non-genetic risk factors to opioid use disorder and related treatment outcomes.

scholarly journals Holistic approach to opioid use disorder: Think nitric oxide!

2019 ◽  
Vol 15 (6) ◽  
pp. 521-555 ◽  
Author(s):  
Marvin A. Sackner, MD ◽  
Jose R. Lopez, MD ◽  
Veronica Banderas, BA TR ◽  
Jose A. Adams. MD
Keyword(s):  
Nitric Oxide ◽  
Holistic Approach ◽  
Cost Effective ◽  
Arterial Disease ◽  
Opioid Use Disorder ◽  
Opioid Addiction ◽  
Opioid Use ◽  
Cost Effective Approach ◽  
Peripheral Arterial ◽  
Endothelial Nitric Oxide

This review deals with opioid addiction, chronic pain, and an innovative, noninvasive technology with simultaneous, beneficial applications for both conditions. This technology, called passive simulated jogging device (GENTLE JOGGER, JD) targets addiction and pain by increasing endothelial nitric oxide (NO) bioavailability. It can be self-administered while sitting or lying without resorting to multitasking thereby allowing watching television or operating a computer while effortless, physical activity is produced from motorized foot pedals repetitively striking a bumper at 175-190 times per minute which adds small pulses to the circulation. This action increases shear stress (friction) to vascular endothelium that stimulates endothelial nitric oxide synthase (eNOS) to increase NO that decreases oxidative stress and inflammation, and, slows accelerated vascular ageing associated with opioids.Since the 1970s, clonidine, lofexidine, and dexmedetomidine have been used off-label to suppress opioid withdrawal symptoms precipitated by excessive release of norepinephrine. These pharmacotherapy aids to withdrawal and tapering opioid dosagadrenoceptor agonists that act through eNOS to inhibit norepinephrine. Increasing NO as with JD and/ or in conjunction with opioid agonists should help stabilization, tapering, withdrawal, and relapses stages of addiction. Nitric oxide as increased with JD technology is antinociceptive as demonstrated in chronic and subacute pain states, viz., fibromyalgia, osteoarthritis, peripheral arterial disease, delayed onset of muscle soreness (DOMS), and sickle cell disease. Jogging device decreases elevated blood pressure that is produced with physical inactivity, a risk to opioid use disorder (OUD). Thus, JD provides holistic, cost-effective approach to opioid addiction as well as chronic and subacute pain.

Responding to the Opioid Epidemic

2021 ◽  
pp. 77-91
Keyword(s):  
Rural Areas ◽  
Complex Disease ◽  
Opioid Use Disorder ◽  
Opioid Addiction ◽  
Rural Populations ◽  
Opioid Epidemic ◽  
Opioid Use ◽  
Medication Assisted Treatment ◽  
Correctional Settings ◽  
Opioid Use Disorders

Chapter 6 examines the complex disease of opioid use disorder and the barriers that exist within the very system designed to help. It also highlights some promising pockets of progress, focusing especially on two environments hit hard by opioid addiction: correctional settings and rural areas. Elizabeth Connolly argues that medication-assisted treatment (MAT) improves outcomes for incarcerated individuals with opioid use disorders and presents examples of successful MAT programs in Massachusetts and Colorado. John Gale explains the complex factors that contribute to opioid addiction among rural populations and why those communities are disproportionately impacted by this epidemic. The chapter concludes with a look at why more progress has not been made.

scholarly journals Co-prescription network reveals social dynamics of opioid doctor shopping

2019 ◽  
Author(s):  
Brea Louise Perry ◽  
Kai-Cheng Yang ◽  
Patrick Kaminski ◽  
Jaehyuk Park ◽  
Michelle Martel ◽  
...  
Keyword(s):  
Social Dynamics ◽  
Social Process ◽  
Healthcare Providers ◽  
Opioid Use Disorder ◽  
Opioid Overdose ◽  
Opioid Use ◽  
Doctor Shopping ◽  
Seeking Behavior ◽  
Occupy Central ◽  
Predicted Risk

This paper examines network prominence in a co-prescription network as an indicator of doctor shopping (i.e., fraudulent solicitation of prescriptions from multiple healthcare providers) for opioids. Using longitudinal data from a large commercially insured population, we construct a network where a tie between patients was weighted by the number of shared opioid prescribers. Given prior research suggesting that doctor shopping may be a social process, we hypothesize that active doctor shoppers will occupy central structural positions in this network. We show that network prominence, operationalized using PageRank, was associated with more opioid prescriptions, higher predicted risk for dangerous morphine dosage, opioid overdose, and opioid use disorder, controlling for number of prescribers and other variables. Moreover, as a patient’s own prominence increased over time, so did their risk for these outcomes, compared to their own average level of risk. These findings point to structural properties of co-prescription networks as a promising indicator of social or strategic drug-seeking behavior and overdose risk.

scholarly journals Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome

2019 ◽  
Author(s):  
Joshua K. Hakimian ◽  
Tien Dong ◽  
Jorge A. Barahona ◽  
Venu Lagishetty ◽  
Suchi Tiwari ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Brain Function ◽  
Opioid Dependence ◽  
Opioid Addiction ◽  
Omega 3 ◽  
Opioid Use ◽  
Dietary Interventions ◽  
Microbiome Composition ◽  
Seeking Behavior ◽  
Novel Model

Opioids are highly addictive substances with a relapse rate of over 90%. While preclinical models of chronic opioid exposure exist for studying opioid dependence, none recapitulate the relapses observed in human opioid addiction. The mechanisms associated with opioid dependence, the accompanying withdrawal symptoms and the relapses that are often observed months or years after opioid dependence are poorly understood. Therefore, we developed a novel model of chronic opioid exposure whereby the level of administration is self-directed with periods of behavior acquisition, maintenance and then extinction alternating with reinstatement. This profile arguably mirrors that seen in humans, with initial opioid use followed by alternating periods of abstinence and relapse. Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 fatty acids such as docosahexaenoic acid (DHA), may reduce substance misuse liability. Using the self-directed intake model, we characterize the observed profile of opioid use and demonstrate that a diet enriched in polyunsaturated fat acids (PUFAs) ameliorates oxycodone-seeking behaviors in the absence of drug availability and reduces anxiety. Guided by the major role gut microbiota have on brain function, neuropathology, and anxiety, we profile the microbiome composition and the effects of chronic opioid exposure and DHA supplementation. We demonstrate that withdrawal of opioids led to a significant depletion in specific microbiota genera whereas DHA supplementation increased microbial richness, phylogenetic diversity, and evenness. Lastly, we examined the activation state of microglia in the striatum and found that DHA supplementation reduced the basal activation state of microglia. These preclinical data suggest that a diet enriched in PUFAs could be used as a treatment to alleviate anxiety induced opioid-seeking behavior and relapse in human opioid addiction.

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