A putative binding model of nitazene derivatives at the μ-opioid receptor
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Clayton, Joseph (ORCID:0000000226525994)↗
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Results for “opioids”
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Kinetics and Mechanism of Fentanyl Dissociation from the μ-Opioid Receptor
Not Available
Mahinthichaichan, Paween↗
Gas Chromatography-Mass Spectrometry Analysis of Synthetic Opioids Belonging to the Fentanyl Class: A Review
Not Available
Valdez, Carlos A.↗
A New Paroxetine-Based GRK2 Inhibitor Reduces Internalization of the [mu]-Opioid Receptor
Abstract not provided
Bouley, Renee A.↗
The aetiology of social deficits within mental health disorders: The role of the immune system and endogenous opioids
Explore the source record for details and available documents.
Sarah J. Charles↗
Agent-Based Model of Combined Community- and Jail-Based Take-Home Naloxone Distribution
Importance Opioid-related overdose accounts for almost 80 000 deaths annually across the US. People who use drugs leaving jails are at particularly high risk for opioid-related overdose and may benefit from take-home naloxone (THN) distribution. Objective To estimate the population impact of THN distribution at jail release to reverse opioid-related overdose among people with opioid use disorders. Design, Setting, and Participants This study developed the agent-based Justice-Community Circulation Model (JCCM) to model a synthetic population of individuals with and without a history of opioid use. Epidemiological data from 2014 to 2020 for Cook County, Illinois, were used to identify parameters pertinent to the synthetic population. Twenty-seven experimental scenarios were examined to capture diverse strategies of THN distribution and use. Sensitivity analysis was performed to identify critical mediating and moderating variables associated with population impact and a proxy metric for cost-effectiveness (ie, the direct costs of THN kits distributed per death averted). Data were analyzed between February 2022 and March 2024. Intervention Modeled interventions included 3 THN distribution channels: community facilities and practitioners; jail, at release; and social network or peers of persons released from jail. Main Outcomes and Measures The primary outcome was the percentage of opioid-related overdose deaths averted with THN in the modeled population relative to a baseline scenario with no intervention. Results Take-home naloxone distribution at jail release had the highest median (IQR) percentage of averted deaths at 11.70% (6.57%-15.75%). The probability of bystander presence at an opioid overdose showed the greatest proportional contribution (27.15%) to the variance in deaths averted in persons released from jail. The estimated costs of distributed THN kits were less than $\$$15 000 per averted death in all 27 scenarios. Conclusions and Relevance This study found that THN distribution at jail release is an economical and feasible approach to substantially reducing opioid-related overdose mortality. Training and preparation of proficient and willing bystanders are central factors in reaching the full potential of this intervention.
Tatara, Eric [Argonne National Laboratory (ANL), A↗
Evaluating kratom alkaloids using PHASE
Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved uses. Kratom contains over forty alkaloids including two partial agonists at the mu opioid receptor, mitragynine and 7-hydroxymitragynine, that have been subjected to the FDA’s scientific and medical evaluation. However, pharmacological and toxicological data for the remaining alkaloids are limited. Therefore, we applied the Public Health Assessment via Structural Evaluation (PHASE) protocol to generate in silico binding profiles for 25 kratom alkaloids to facilitate the risk evaluation of kratom. PHASE demonstrates that kratom alkaloids share structural features with controlled opioids, indicates that several alkaloids bind to the opioid, adrenergic, and serotonin receptors, and suggests that mitragynine and 7-hydroxymitragynine are the strongest binders at the mu opioid receptor. Subsequently, the in silico binding profiles of a subset of the alkaloids were experimentally verified at the opioid, adrenergic, and serotonin receptors using radioligand binding assays. The verified binding profiles demonstrate the ability of PHASE to identify potential safety signals and provide a tool for prioritizing experimental evaluation of high-risk compounds.
60 APPLIED LIFE SCIENCES↗
Structural modification of fentanyls for their retrospective identification by gas chromatographic analysis using chloroformate chemistry
Abstract The one-step breakdown and derivatization of a panel of nine fentanyls to yield uniquely tagged products that can be detected by Electron Ionization Gas Chromatography-Mass Spectrometry (EI-GC-MS) is presented. The method involves the treatment of the synthetic opioids with 2,2,2-trichloroethoxycarbonyl chloride (TrocCl) at 60 °C for 3 h in dichloromethane and furnishes two products from one fentanyl molecule that can be used to retrospectively identify the original opioid. Parameters that were studied and fully optimized for the method included temperature, solvent, nature of scavenging base and reaction time. One of the two resulting products from the reaction bears the trichloroethoxycarbonyl (Troc) tag attached to the norfentanyl portion of the original opioid and greatly aids in the opioid detection and identification process. The methodology has been applied to the chemical modification of a panel of nine fentanyls and in all cases the molecular ion peak for the Troc-norfentanyl product bearing the distinctive trichloroethyl isotopic signature can be clearly observed. The method’s LLOD was determined to be 10 ng/mL while its LLOQ was found to be 20 ng/mL. This methodology represents the first application of chloroformates in the chemical modification of this class of synthetic opioids that are notoriously inert to common derivatization strategies available for GC–MS analysis.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Opiate Sensitivity in Fruit Flies
Substance use disorder is a debilitating clinical condition in which behavioral dependence results from biological, environmental, genetic, and psychosocial factors. An epidemic surrounding the use and abuse of opioids is ravaging the world. While considerable efforts have explored the social drivers of addiction, a deeper understanding of biological causes and genetic vulnerabilities, preventative interventions, and effective treatments, have all proven elusive. This perspective article aims to remind readers that addictive natural compounds such as cocaine, nicotine, cathinone, or morphine, evolved as defensive metabolites to deter insect herbivory. The molecular mechanisms underlying motivational seeking and learning/reward show remarkable conservation since their early emergence in bilateral metazoans. An extended coevolutionary arms race subsequently weaponized these compounds into disruptors of learning, motivation, and incentivized attention. When plant chemical defenses attack insect physiology, humans are rendered susceptible due to strong conservation in the underlying molecular machinery. This perspective addresses the paradox that opiates were shaped to target insect neuropharmacology, even though this taxon appears to lack the recognized opioid receptor clade of mammals. We argue that the link is to be found in the allatostatin receptor, a basal ortholog of opioid receptors. Moreover, preliminary evidence indicates that morphine reduces Drosophila feeding and locomotion, concordant with a purported role as a defensive compound reducing herbivory. An implementation via allatostatin-mediated mechanisms is likely. This research argues for a broader heuristic perspective of substance abuse and a recognition of the evolutionary constraints that have likely shaped the biological drivers of opioid sensitivity and of its behavioral targets.
59 BASIC BIOLOGICAL SCIENCES↗
Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children
Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO 2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.
60 APPLIED LIFE SCIENCES↗
Effect of morphine on sympathetic nerve activity in humans
There are conflicting reports for the role of endogenous opioids on sympathetic and cardiovascular responses to exercise in humans. A number of studies have utilized naloxone (an opioid-receptor antagonist) to investigate the effect of opioids during exercise. In the present study, we examined the effect of morphine (an opioid-receptor agonist) on sympathetic and cardiovascular responses at rest and during isometric handgrip (IHG). Eleven subjects performed 2 min of IHG (30% maximum) followed by 2 min of postexercise muscle ischemia (PEMI) before and after systemic infusion of morphine (0.075 mg/kg loading dose + 1 mg/h maintenance) or placebo (saline) in double-blinded experiments on separate days. Morphine increased resting muscle sympathetic nerve activity (MSNA; 17 +/- 2 to 22 +/- 2 bursts/min; P < 0.01) and increased mean arterial pressure (MAP; 87 +/- 2 to 91 +/- 2 mmHg; P < 0.02), but it decreased heart rate (HR; 61 +/- 4 to 59 +/- 3; P < 0.01). However, IHG elicited similar increases for MSNA, MAP, and HR between the control and morphine trial (drug x exercise interaction = not significant). Moreover, responses to PEMI were not different. Placebo had no effect on resting, IHG, and PEMI responses. We conclude that morphine modulates cardiovascular and sympathetic responses at rest but not during isometric exercise.
Non-NASA Center↗
Machine Learning Discrimination and Ultrasensitive Detection of Fentanyl Using Gold Nanoparticle-Decorated Carbon Nanotube-Based Field-Effect Transistor Sensors
The opioid overdose crisis is a global health challenge. Fentanyl, an exceedingly potent synthetic opioid, has emerged as a leading contributor to the surge in opioid-related overdose deaths. The surge in overdose fatalities, particularly due to illicitly manufactured fentanyl and its contamination of street drugs, emphasizes the urgency for drug-testing technologies that can quickly and accurately identify fentanyl from other drugs and quantify trace amounts of fentanyl. In this paper, gold nanoparticle (AuNP)-decorated single-walled carbon nanotube (SWCNT)-based field-effect transistors (FETs) are utilized for machine learning-assisted identification of fentanyl from codeine, hydrocodone, and morphine. The unique sensing performance of fentanyl led to use machine learning approaches for accurate identification of fentanyl. Employing linear discriminant analysis (LDA) with a leave-one-out cross-validation approach, a validation accuracy of 91.2% is achieved. Meanwhile, density functional theory (DFT) calculations reveal the factors that contributed to the enhanced sensitivity of the Au-SWCNT FET sensor toward fentanyl as well as the underlying sensing mechanism. Finally, fentanyl antibodies are introduced to the Au-SWCNT FET sensor as specific receptors, expanding the linear range of the sensor in the lower concentration range, and enabling ultrasensitive detection of fentanyl with a limit of detection at 10.8 fg mL –1 .
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block
Buprenorphine is a μ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QT C prolongation that crosses the 10 msec threshold of regulatory concern was observed at a supratherapeutic dose in two thorough QT studies for the transdermal buprenorphine product BUTRANS®. Because QT C prolongation can be associated with Torsades de Pointes (TdP), a rare but potentially fatal ventricular arrhythmia, these results have led to further investigation of the electrophysiological effects of buprenorphine. Drug-induced QT C prolongation and TdP are most commonly caused by acute inhibition of hERG current (I hERG ) that contribute to the repolarizing phase of the ventricular action potentials (APs). Concomitant inhibition of inward late Na + (I NaL ) and/or L-type Ca 2+ (I CaL ) current can offer some protection against proarrhythmia. Therefore, we characterized the effects of buprenorphine and its major metabolite norbuprenorphine on cardiac hERG, Ca 2+ , and Na + ion channels, as well as cardiac APs. For comparison, methadone, a MOR agonist associated with QT C prolongation and high TdP risk, and naltrexone and naloxone, two opioid receptor antagonists, were also studied. Whole cell recordings were performed at 37°C on cells stably expressing hERG, Ca V 1.2, and Na V 1.5 proteins. Microelectrode array (MEA) recordings were made on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The results showed that buprenorphine, norbuprenorphine, naltrexone, and naloxone had no effect on I hERG , I CaL , I NaL , and peak Na + current (I NaP ) at clinically relevant concentrations. In contrast, methadone inhibited I hERG , I CaL , and I NaL . Experiments on iPSC-CMs showed a lack of effect for buprenorphine, norbuprenorphine, naltrexone, and naloxone, and delayed repolarization for methadone at clinically relevant concentrations. The mechanism of QT C prolongation is opioid moiety-specific. This remains undefined for buprenorphine, while for methadone it involves direct hERG channel block. There is no evidence that buprenorphine use is associated with TdP. Whether this lack of TdP risk can be generalized to other drugs with QT C prolongation not mediated by acute hERG channel block warrants further study.
59 BASIC BIOLOGICAL SCIENCES↗
Accurate prediction of terahertz spectra of molecular crystals of fentanyl and its analogs
Fentanyl is a potent synthetic opioid pain reliever with a high bioavailability that can be used as prescription anesthetic. Rapid identification via non-contact methods of both known and emerging opioid substances in the fentanyl family help identify the substances and enable rapid medical attention. We apply PBEh-3c method to identify vibrational normal modes from 0.01 to 3 THz in solid fentanyl and its selected analogs. The molecular structure of each fentanyl analog and unique arrangement of H-bonds and dispersion interactions significantly change crystal packing and is subsequently reflected in the THz spectrum. Further, the study of THz spectra of a series of stereoisomers shows that small changes in molecular structure results in distinct crystal packing and significantly alters THz spectra as well. We discuss spectral features of synthetic opioids with higher potency than conventional fentanyl such as ohmefentanyl and sufentanil and discover the pattern of THz spectra of fentanyl analogs.
42 ENGINEERING↗
Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl
Abstract Cyclodextrins (CDs) have been previously shown to display modest equilibrium binding affinities ( K a ~ 100–200 M -1 ) for the synthetic opioid analgesic fentanyl. In this work, we describe the synthesis of new CDs possessing extended thioalkylcarboxyl or thioalkylhydroxyl moieties and assess their binding affinity towards fentanyl hydrochloride. The optimal CD studied displays a remarkable affinity for the opioid of K a = 66,500 M −1 , the largest value reported for such an inclusion complex to date. One dimensional 1 H Nuclear Magnetic Resonance (NMR) as well as Rotational Frame Overhauser Spectroscopy (2D-ROESY) experiments supported by molecular dynamics (MD) simulations suggest an unexpected binding behavior, with fentanyl able to bind the CD interior in one of two distinct orientations. Binding energies derived from the MD simulations work correlate strongly with NMR-derived affinities highlighting its utility as a predictive tool for CD candidate optimization. The performance of these host molecules portends their utility as platforms for medical countermeasures for opioid exposure, as biosensors, and in other forensic science applications.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Stressed to death: implication of lymphocyte apoptosis for psychoneuroimmunology
Psychological and physical stressors best exemplify the intercommunication of the immune and the nervous systems. It has been shown that stress significantly impacts leukocyte cellularity and immune responses and alters susceptibility to various diseases. While acute stress has been shown to enhance immune responses, chronic stress often leads to immunosuppression. Among many criteria examined upon exposure to chronic stress, the reduction in lymphocyte mitogenic response and lymphocyte cellularity are commonly assessed. We have reported that chronic restraint stress could induce lymphocyte reduction, an effect dependent on endogenous opioids. Interestingly, the effect of endogenous opioids was found to be exerted through increasing the expression of a cell death receptor, Fas, and an increased sensitivity of lymphocytes to apoptosis. Stress-induced lymphocyte reduction was not affected by adrenalectomy. In this review, based on available literature and our recent data, we will discuss the role of the hypothalamic-pituitary-adrenal axis and endogenous opioids and examine the mechanisms by which chronic stress modulates lymphocyte apoptosis.
Review Literature↗
Incorporating space and time into random forest models for analyzing geospatial patterns of drug-related crime incidents in a major U.S. metropolitan area
The opioid crisis has hit American cities hard, and research on spatial and temporal patterns of drug-related activities including detecting and predicting clusters of crime incidents involving particular types of drugs is useful for distinguishing hot zones where drugs are present that in turn can further provide a basis for assessing and providing related treatment services. In this study, we investigated spatiotemporal patterns of more than 52,000 reported incidents of drug-related crime at block group granularity in Chicago, IL between 2016 and 2019. We applied a space-time analysis framework and machine learning approaches to build a model using training data that identified whether certain locations and built environment and sociodemographic factors were correlated with drug-related crime incident patterns, and establish the top contributing factors that underlaid the trends. Space and time, together with multiple driving factors, were incorporated into a random forest model to analyze these changing patterns. We accommodated both spatial and temporal autocorrelation in the model learning process to assist with capturing the changes over time and tested the capabilities of the space-time random forest model by predicting drug-related activity hot zones. Overall, we focused particularly on crime incidents that involved heroin and synthetic drugs as these have been key drug types that have highly impacted cities during the opioid crisis in the U.S.
97 MATHEMATICS AND COMPUTING↗