The placenta as a target of opioid drugs

2022 ◽  
Author(s):  
Cheryl S Rosenfeld
Keyword(s):  
Opioid Use Disorder ◽  
Congenital Defects ◽  
Opioid Use ◽  
Endogenous Opioid System ◽  
Endogenous Opioid ◽  
Wide Range ◽  
Opioid Drugs ◽  
Hospital Stays ◽  
Control Pain ◽  
Opioid Withdrawal Syndrome

Abstract Opioid drugs are analgesics increasingly being prescribed to control pain associated with a wide range of causes. Usage of pregnant women has dramatically increased in the past decades. Neonates born to these women are at risk for neonatal abstinence syndrome (NAS, also referred termed neonatal opioid withdrawal syndrome, NOWS). Negative birth outcomes linked with maternal opioid use disorder include compromised fetal growth, premature birth, reduced birthweight, and congenital defects. Such infants require lengthier hospital stays necessitating rising health care costs, and they are at greater risk for neurobehavioral and other diseases. Thus, it is essential to understand the genesis of such disorders. As the primary communication organ between mother and conceptus, the placenta itself is susceptible to opioid effects but may be key to understanding how these drugs affect long-term offspring health and how poor health outcomes may be ameliorated in utero. In this review, we will consider the evidence that placental responses are regulated through an endogenous opioid system. However, maternal consumption of opioid drugs can also bind and act through opioid receptors express by trophoblast (TB) cells of the placenta. Thus, we will also discuss the current human and rodent studies that have examined the effects of opioids on the placenta. These drugs might affect placental hormones associated with maternal recognition of pregnancy, including placental lactogens and human chorionic gonadotropin (hCG) in rodents and humans, respectively. A further understanding of how such drugs affect the placenta may open up new avenues for early diagnosis and remediation approaches.

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.

Maternal opioid use disorder: Placental transcriptome analysis for neonatal opioid withdrawal syndrome

Genomics ◽  
2021 ◽  
Author(s):  
Uppala Radhakrishna ◽  
Swapan K. Nath ◽  
Sangeetha Vishweswaraiah ◽  
Lavanya V. Uppala ◽  
Ariadna Forray ◽  
...  
Keyword(s):  
Transcriptome Analysis ◽  
Withdrawal Syndrome ◽  
Opioid Use Disorder ◽  
Opioid Withdrawal ◽  
Opioid Use ◽  
Opioid Withdrawal Syndrome

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 Impaired empathy and increased anger following social exclusion in non-intoxicated opioid users

2019 ◽  
Vol 237 (2) ◽  
pp. 419-430
Author(s):  
Molly Carlyle ◽  
Megan Rowley ◽  
Tobias Stevens ◽  
Anke Karl ◽  
Celia J. A. Morgan
Keyword(s):  
Social Functioning ◽  
Social Exclusion ◽  
Positive Emotions ◽  
Physiological Responses ◽  
Cognitive Empathy ◽  
Self Report ◽  
Opioid Use ◽  
Endogenous Opioid System ◽  
Endogenous Opioid ◽  
Opioid Users

Abstract Rationale Social functioning is modulated by the endogenous opioid system. In opioid use disorder, social functioning appears disrupted, but little research has delineated the nature of these deficits and their relationship to acute opioid use. Objectives The current study aimed to assess both emotional and cognitive empathy, along with subjective and physiological responses to social exclusion in opioid users who were either acutely intoxicated or non-intoxicated from using opioids. Methods Individuals on an opioid substitution medication (OSM) were divided into ‘intoxicated users’ (had taken their OSM the same day as testing, n = 20) and ‘non-intoxicated users’ (had taken their OSM > 12 h ago, n = 20) and compared with opioid-naïve controls (n = 24). Empathy was assessed using the multifaceted empathy test and self-report questionnaire. Participants also underwent a period of social exclusion (Cyberball Game) and completed measures of mood and physiological responses (salivary cortisol and heart rate). Results Non-intoxicated users had significantly lower emotional empathy (the ability to experience others’ emotions), as well as greater anger after social exclusion when compared with the intoxicated users and controls. Anger did not change with social exclusion in the intoxicated user group and cortisol levels were lower overall. Conclusions Reduced ability to spontaneously share the emotions of others was reported in non-intoxicated users, particularly regarding positive emotions. There was some support for the idea of hyperalgesia to social pain, but this was restricted to an enhanced anger response in non-intoxicated users. Equivalent rates of empathy between the intoxicated users and controls could indicate some remediating effects of acute opioids.

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 The Role of Quality of Education in Neurocognitive Functioning in a Diverse Sample with Chronic Opioid Use Disorder

2019 ◽  
Vol 34 (7) ◽  
pp. 1269-1269
Author(s):  
J Olsen ◽  
J Arnsten ◽  
T Scott ◽  
F Arias ◽  
C Zhang ◽  
...  
Keyword(s):  
Executive Functioning ◽  
Opioid Use Disorder ◽  
Reading Level ◽  
Quality Of Education ◽  
Opioid Use ◽  
Significant Group ◽  
Wide Range ◽  
Chronic Opioid Use

Abstract Objective Literacy is a proxy for quality of education (QoE) and mediates ethnicity-related differences in neurocognitive (NC) performance in some populations (Manly et al., 2002; Rivera Mindt et al., 2008). However, it is unknown whether this relationship exists in the context of chronic opioid use disorder (OUD). This study examined the role of ethnicity, QoE, opioid use severity, and depression in predicting NC performance in a diverse sample of persons with OUD. Participants and Method This cross-sectional study included 74 adults with OUD (Age M = 40.3 [SD = 10.5]; Education M = 11.3 [2.5]; 24% female; 68% Latinx and 32% Non-Latinx White [NLW]). All participants completed comprehensive NC testing and psychiatric/substance use questionnaires. Variables included ethnicity (Latinx vs. Non-Latinx White), years of education, QoE (Wide Range Achievement Test, Third Edition; WRAT-3 Reading Standard Scores), opioid use severity (high vs. low OAT dose), current depression (Beck Depression Inventory, Second Edition; BDI-II Total Score), and demographically-corrected NC T-scores were computed and used for average domain T-scores (e.g., learning, memory, verbal fluency, executive function). Bivariate and ANCOVA analyses were used to compare ethnic groups. Results There were no significant group differences on opioid use severity or current depression (p’s > .05). However, compared to the NLW group, the Latinx group had lower years of education (M = 10.9 [SD = 1.7] vs. M = 12.2 [SD = 3.5]; t[72)] = 2.1, p < .05), QoE (M = 83.1 [SD = 13.6] vs. M = 94.8 [SD = 9.4]; t[72] = 3.8, p < .001), executive functioning (M = 42.0 [SD = 6.5] vs. M = 45.8 [SD = 8.5]; t[72) = 2.1, p < .05), and learning (M = 32.2 [SD = 8.2] vs. M = 37.8 [SD = 8.7]; t[72)] = 2.7, p < .05), with medium to large effect sizes (Cohen’s d > .50). The overall effect of ethnicity became non-significant for executive functioning after accounting for QoE (F[2,70] = 10.0, p = .002) and years of education (F[2,70)] = 16.8, p < .001). Conclusions The current study found that accounting for years of education and QoE attenuates some differences in NC performance between Latinx and Non-Latinx participants. References Manly, J. J., Jacobs, D. M., Touradji, P., Small, S. A., & Stern, Y. (2002). Reading level attenuates differences in neuropsychological test performance between African American and White elders. Journal of the International Neuropsychological Society, 8(3), 341-348. Mindt, M. R., Arentoft, A., Germano, K. K., D’Aquila, E., Scheiner, D., Pizzirusso, M., ... & Gollan, T. H. (2008). Neuropsychological, cognitive, and theoretical considerations for evaluation of bilingual individuals. Neuropsychology review, 18(3), 255-268.

scholarly journals Opioids and the developing brain: time to rethink perinatal care for infants of opioid-dependent mothers

2021 ◽  
pp. fetalneonatal-2020-320102
Author(s):  
James P Boardman ◽  
Helen Mactier ◽  
Lori A Devlin
Keyword(s):  
Perinatal Care ◽  
Opioid Use Disorder ◽  
Visual Development ◽  
Opioid Use ◽  
Health Crisis ◽  
Long Term Follow Up ◽  
And Function ◽  
Opioid Withdrawal Syndrome ◽  
Infant Brain Development

Illicit use of opioids is a global health crisis with major implications for women and children. Strategies for managing opioid use disorder (OUD) in pregnancy have been tested over the past 40 years, but studies have focused on maternal and pregnancy outcomes, with less attention given to long-term follow-up of exposed children. Here, we provide a narrative review of recent advances in the assessment and management of neonatal opioid withdrawal syndrome (NOWS), and we summarise evidence from multiple domains—neuroimaging, electrophysiology, visual development and function, neurodevelopment, behaviour, cognition and education—which suggests that prenatal opioid exposure modifies child development. Further studies are required to determine the optimal management of pregnant women with OUD and babies with NOWS. We identify knowledge gaps and suggest that future study designs should evaluate childhood outcomes, including infant brain development and long-term neurocognitive and visual function.

Stress activates pronociceptive endogenous opioid signalling in DRG neurons during chronic colitis

Gut ◽  
2016 ◽  
Vol 66 (12) ◽  
pp. 2121-2131 ◽  
Author(s):  
Raquel Guerrero-Alba ◽  
Eduardo E Valdez-Morales ◽  
Nestor N Jimenez-Vargas ◽  
Cintya Lopez-Lopez ◽  
Josue Jaramillo-Polanco ◽  
...  
Keyword(s):  
G Protein ◽  
Imaging Techniques ◽  
Stress Hormones ◽  
Endogenous Opioids ◽  
Opioid Use ◽  
Chronic Colitis ◽  
Drg Neurons ◽  
Endogenous Opioid System ◽  
Endogenous Opioid ◽  
Stress Changes

Aims and backgroundPsychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways.MethodsMouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca2+imaging techniques.ResultsSupernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca2+responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neurons from an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein βϒ subunits.ConclusionsStress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.

Supportive-Expressive Psychodynamic Psychotherapy for the Treatment of Opioid Use Disorder

2021 ◽  
Vol 49 (3) ◽  
pp. 388-403
Author(s):  
William H. Gottdiener
Keyword(s):  
Substance Use ◽  
Substance Use Disorders ◽  
Psychodynamic Psychotherapy ◽  
The United States ◽  
Opioid Use Disorder ◽  
Opioid Use ◽  
Self Medication ◽  
The Core ◽  
Wide Range ◽  
Opioid Use Disorders

The United States is in the midst of an opioid epidemic with over 200,000 deaths per year due to opioid overdoses. There are numerous psychotherapeutic and medication-assisted approaches to treating opioid use disorder, but psychodynamic approaches remain underappreciated and underused. The self-medication hypothesis of substance use disorders is a psychodynamic model, which argues that all substance use disorders serve to defend against intolerable affects. In the case of opioid use disorders, opioids are thought to help defend against intense intolerable feelings of rage and depression associated with trauma. Supportive-expressive psychodynamic psychotherapy is an empirically supported psychodynamic treatment for a wide range of psychological problems, including opioid use disorders. Supportive-expressive psychodynamic psychotherapy focuses on transference analysis using an operationalized conceptualization of transference called the core conflictual relational theme method. This article describes supportive-expressive psychodynamic psychotherapy for opioid use disorders and provides clinical examples of its use in practice. The article describes and illustrates the three phases of supportive-expressive psychodynamic psychotherapy, the formulation of the core conflictual relationship theme, how it is applied when treating people with an opioid use disorder, and how supportive-expressive psychodynamic psychotherapy can be used with other therapies, such as medication-assisted treatments and 12-step programs. Last, this article encourages psychodynamic therapists who are not involved in treating people with an opioid use disorder to engage in treating people with one using supportive-expressive psychodynamic psychotherapy.

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