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.

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 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 The expression of delta opioid receptor mRNA in adult male zebra finches (Taenopygia guttata)

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256599
Author(s):  
Pooja Parishar ◽  
Neha Sehgal ◽  
Soumya Iyengar
Keyword(s):  
Opioid Receptors ◽  
Sequence Similarity ◽  
Expression Patterns ◽  
Auditory Pathway ◽  
Zebra Finches ◽  
Endogenous Opioid System ◽  
Endogenous Opioid ◽  
High Sequence Similarity ◽  
Brain Functions ◽  
Song Control

The endogenous opioid system is evolutionarily conserved across reptiles, birds and mammals and is known to modulate varied brain functions such as learning, memory, cognition and reward. To date, most of the behavioral and anatomical studies in songbirds have mainly focused on μ-opioid receptors (ORs). Expression patterns of δ-ORs in zebra finches, a well-studied species of songbird have not yet been reported, possibly due to the high sequence similarity amongst different opioid receptors. In the present study, a specific riboprobe against the δ-OR mRNA was used to perform fluorescence in situ hybridization (FISH) on sections from the male zebra finch brain. We found that δ-OR mRNA was expressed in different parts of the pallium, basal ganglia, cerebellum and the hippocampus. Amongst the song control and auditory nuclei, HVC (abbreviation used as a formal name) and NIf (nucleus interfacialis nidopallii) strongly express δ-OR mRNA and stand out from the surrounding nidopallium. Whereas the expression of δ-OR mRNA is moderate in LMAN (lateral magnocellular nucleus of the anterior nidopallium), it is low in the MSt (medial striatum), Area X, DLM (dorsolateral nucleus of the medial thalamus), RA (robust nucleus of the arcopallium) of the song control circuit and Field L, Ov (nucleus ovoidalis) and MLd (nucleus mesencephalicus lateralis, pars dorsalis) of the auditory pathway. Our results suggest that δ-ORs may be involved in modulating singing, song learning as well as spatial learning in zebra finches.

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 Basic Opioid Pharmacology — An Update

2020 ◽  
Vol 14 (2) ◽  
pp. 115-121 ◽  
Author(s):  
Arul James ◽  
John Williams
Keyword(s):  
Opioid Receptors ◽  
The United States ◽  
Opioid Use Disorder ◽  
G Protein Coupled Receptors ◽  
Opioid Use ◽  
Synthetic Compounds ◽  
Analgesic Agents ◽  
National Emergency ◽  
G Protein Coupled ◽  
Receptor Family

Opioids are a group of analgesic agents commonly used in clinical practice. The three classical opioid receptors are MOP, DOP and KOP. The NOP (N/OFQ) receptor is considered to be a non-opioid branch of the opioid receptor family. Opioid receptors are G-protein-coupled receptors which cause cellular hyperpolarisation when bound to opioid agonists. Opioids may be classified according to their mode of synthesis into alkaloids, semi-synthetic and synthetic compounds. Opioid use disorder (OUD) is an emerging issue and important lessons can be learnt from the United States where opioid epidemic was declared as a national emergency in 2017.

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 An opioid-like system regulating feeding behavior in C. elegans

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Mi Cheong Cheong ◽  
Alexander B Artyukhin ◽  
Young-Jai You ◽  
Leon Avery
Keyword(s):  
Caenorhabditis Elegans ◽  
Feeding Behavior ◽  
Opioid Receptors ◽  
Motor Neurons ◽  
Sequence Similarity ◽  
Rnai Screen ◽  
Endogenous Opioid System ◽  
Endogenous Opioid ◽  
C Elegans ◽  
Opioid Neuropeptides

Neuropeptides are essential for the regulation of appetite. Here we show that neuropeptides could regulate feeding in mutants that lack neurotransmission from the motor neurons that stimulate feeding muscles. We identified nlp-24 by an RNAi screen of 115 neuropeptide genes, testing whether they affected growth. NLP-24 peptides have a conserved YGGXX sequence, similar to mammalian opioid neuropeptides. In addition, morphine and naloxone respectively stimulated and inhibited feeding in starved worms, but not in worms lacking NPR-17, which encodes a protein with sequence similarity to opioid receptors. Opioid agonists activated heterologously expressed NPR-17, as did at least one NLP-24 peptide. Worms lacking the ASI neurons, which express npr-17, did not response to naloxone. Thus, we suggest that Caenorhabditis elegans has an endogenous opioid system that acts through NPR-17, and that opioids regulate feeding via ASI neurons. Together, these results suggest C. elegans may be the first genetically tractable invertebrate opioid model.

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