Single nucleus transcriptomic analysis of rat nucleus accumbens reveals cell type-specific patterns of gene expression associated with volitional morphine intake DOI Creative Commons
Benjamin C. Reiner,

Yafang Zhang,

Lauren M. Stein

et al.

Translational Psychiatry, Journal Year: 2022, Volume and Issue: 12(1)

Published: Sept. 8, 2022

Abstract Opioid exposure is known to cause transcriptomic changes in the nucleus accumbens (NAc). However, no studies date have investigated cell type-specific associated with volitional opioid taking. Here, we use single RNA sequencing (snRNAseq) comprehensively characterize alterations of NAc transcriptome rats self-administering morphine. One cohort male Brown Norway was injected acute morphine (10 mg/kg, i.p.) or saline. A second allowed self-administer intravenous (1.0 mg/kg/infusion) for 10 consecutive days. Each morphine-experienced rat paired a yoked saline control rat. snRNAseq libraries were generated from punches and used identify gene expression We identified 1106 differentially expressed genes (DEGs) group, compared 2453 DEGs self-administration across 27 distinct clusters. Importantly, 1329 that specific self-administration. novel clusters astrocytes, oligodendrocytes, D1R- D2R-expressing medium spiny neurons NAc. Cell included Rgs9 , Celf5 Oprm1 Pde10a . Upregulation validated by RNAscope. Approximately 85% all oligodendrocyte DEGs, nearly which taking, two subtypes. Bioinformatic analyses upstream regulatory mechanisms observed downstream signaling pathways, including both previously molecular pathways. These findings show taking highlight striatal populations substrates could be targeted reduce compulsive

Language: Английский

Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment DOI Creative Commons
Sandra D. Comer, Catherine M. Cahill

Neuroscience & Biobehavioral Reviews, Journal Year: 2018, Volume and Issue: 106, P. 49 - 57

Published: Dec. 5, 2018

Language: Английский

Citations

225
Respiratory depression and brain hypoxia induced by opioid drugs: Morphine, oxycodone, heroin, and fentanyl DOI Creative Commons
Eugene A. Kiyatkin

Neuropharmacology, Journal Year: 2019, Volume and Issue: 151, P. 219 - 226

Published: Feb. 5, 2019

Language: Английский

Citations

134
Existing and Future Drugs for the Treatment of the Dark Side of Addiction DOI
George F. Koob,

Barbara J. Mason

The Annual Review of Pharmacology and Toxicology, Journal Year: 2015, Volume and Issue: 56(1), P. 299 - 322

Published: Oct. 30, 2015

The identification of a heuristic framework for the stages addiction cycle that are linked to neurocircuitry changes in pathophysiology includes binge/intoxication stage, withdrawal/negative affect and preoccupation/anticipation (craving) which represent neuroadaptations three neurocircuits (basal ganglia, extended amygdala, frontal cortex, respectively). excellent validated animal models, development human laboratory an enormous surge our understanding neuropharmacological mechanisms have provided revisionist view emphasizes loss brain reward function gain stress drive negative reinforcement (the dark side addiction) as key compulsive drug seeking. Reversing not only explains much existing successful pharmacotherapies but also points vast new opportunities future medications alleviate this major source suffering.

Language: Английский

Citations

108
Oxycodone self-administration in male and female rats DOI
Maria Mavrikaki, Marco Pravetoni, Sarah Page

et al.

Psychopharmacology, Journal Year: 2017, Volume and Issue: 234(6), P. 977 - 987

Published: Jan. 26, 2017

Language: Английский

Citations

104
Lorcaserin Suppresses Oxycodone Self-Administration and Relapse Vulnerability in Rats DOI
Harshini Neelakantan, Erica Holliday,

Robert G. Fox

et al.

ACS Chemical Neuroscience, Journal Year: 2017, Volume and Issue: 8(5), P. 1065 - 1073

Published: Jan. 21, 2017

Opioid use disorder (OUD) is a major public health problem. High relapse rates and poor treatment retention continue to pose challenges in OUD treatment. Of the abused opioids, oxycodone well described maintain self-administration evoke durable conditioned responses ("cue reactivity") that result from pairing of opioid-related stimuli (e.g., paraphernalia) with repeated abuse. Serotonin (5-HT) neurotransmission, particularly through 5-HT2C receptor (5-HT2CR), regulates psychostimulant reward cue reactivity, present experiments, we investigated hypothesis selective 5-HT2CR agonist lorcaserin, which approved by United States Food Drug Administration (FDA) for obesity, will suppress oxycodone-associated reactivity rats. We found lorcaserin inhibited intake, an effect blocked antagonist SB242084. Lorcaserin also decreased responding discrete complex previously associated delivery (i.e., stimulus lights, infusion pump sounds) both abstinence extinction-reinstatement models. The selected dose range (0.25-1 mg/kg) does not overtly alter spontaneous behaviors nor operant on inactive levers study. Taken together, ability reduce decrease highlights therapeutic potential OUD.

Language: Английский

Citations

91
Oxycodone in the Opioid Epidemic: High ‘Liking’, ‘Wanting’, and Abuse Liability DOI
Cherkaouia Kibaly, Jacob A. Alderete, Steven Liu

et al.

Cellular and Molecular Neurobiology, Journal Year: 2020, Volume and Issue: 41(5), P. 899 - 926

Published: Nov. 27, 2020

Language: Английский

Citations

78
Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences DOI Open Access
Renata C.N. Marchette, Erika R. Carlson,

Emma V. Frye

et al.

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2023, Volume and Issue: 385(2), P. 117 - 134

Published: Feb. 24, 2023

The opioid overdose death toll in the United States is an ongoing public health crisis. We characterized magnitude and duration of respiratory depression, leading cause cases, induced by heroin or fentanyl development tolerance male female rats. used whole-body plethysmography to first establish dose-response curves recording breathing for 60 minutes post-intravenous injection. then tested acute over several weeks chronic with challenge. Heroin each provoked dose-dependent depression. caused prolonged (45–60 minute) depression rats, decreased frequency, tidal volume, minute ventilation increased inspiratory time apneic pause. Fentanyl produced similar changes a shorter (10–15 minutes). High-dose robust that was slightly more severe females and, when given intermittently (acute doses 2 3 apart), did not lead tolerance. In contrast, delivered osmotic minipump resulted heroin, This effect persisted during withdrawal males only. Our model experimental design will allow investigation neurobiology opioid-induced testing potential therapeutics reverse stimulate breathing.

SIGNIFICANCE STATEMENT

potent had producing than both sexes, whereas rats were sensitive heroin-induced Tolerance/cross-tolerance develops administration but minimized long interadministration intervals.

Language: Английский

Citations

33
Docking 14 million virtual isoquinuclidines against the mu and kappa opioid receptors reveals dual antagonists-inverse agonists with reduced withdrawal effects DOI Creative Commons
Seth F. Vigneron, Shohei Ohno, João Braz

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Abstract Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration targeted isoquinuclidines. These “natural-product-like” rare in current functionally congested, making them as receptor probes. Using modular, four-component scheme, built docked virtual over 14.6 million isoquinuclidines against both µ- κ -opioid receptors (MOR KOR, respectively). Synthesis experimental testing 18 prioritized compounds found nine with low µM affinities. Structure-based optimization low- sub- nM antagonists inverse agonists targeting receptors. Cryo-electron microscopy (cryoEM) structures illuminate origins activity on each target. In mouse behavioral studies, member series joint MOR-antagonist KOR-inverse-agonist reversed morphine-induced analgesia, phenocopying MOR-selective anti-overdose agent naloxone. Encouragingly, new molecule induced less severe opioid-induced withdrawal symptoms compared to naloxone during precipitation, did not induce conditioned-place aversion, likely reflecting reduction dysphoria due compound’s KOR-inverse agonism. The strengths weaknesses bespoke docking, for opioid polypharmacology, will be considered.

Language: Английский

Citations

1
Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine DOI

James E. Zadina,

Mark R. Nilges,

Jenny Morgenweck

et al.

Neuropharmacology, Journal Year: 2015, Volume and Issue: 105, P. 215 - 227

Published: Dec. 31, 2015

Language: Английский

Citations

88
Chronic EtOH effects on putative measures of compulsive behavior in mice DOI
Anna K. Radke, Nicholas J. Jury,

Adrina Kocharian

et al.

Addiction Biology, Journal Year: 2015, Volume and Issue: 22(2), P. 423 - 434

Published: Dec. 21, 2015

Abstract Addictions, including alcohol use disorders, are characterized by the loss of control over drug seeking and consumption, but neural circuits signaling mechanisms responsible for transition from controlled to uncontrolled abuse remain incompletely understood. Prior studies have shown that ‘compulsive‐like’ behaviors in rodents, example, persistent responding ethanol (EtOH) despite punishment, increased after chronic exposure EtOH. The main goal current study was assess effects intermittent EtOH (CIE) on multiple, putative measures compulsive‐like C57BL/6 J mice. Mice were exposed two or four weekly cycles CIE then, post‐withdrawal, tested progressive ratio EtOH, sustained during signaled unavailability (footshock) punished suppression Results showed mice exhibited attenuated as compared with air‐exposed controls. By contrast, affected neither food reward‐seeking behavior, nor other seeking. Ex vivo reverse transcription polymerase chain reaction analysis brain tissue found reduced sensitivity accompanied a significant increase gene expression GluN1 GluN2A subunits N ‐methyl‐ d ‐aspartate receptor, specifically medial orbitofrontal cortex. Moreover, slice electrophysiological revealed receptor‐mediated currents cortex test‐naïve Collectively, findings add growing body evidence demonstrating fosters resistance association adaptations cortical glutamatergic transmission.

Language: Английский

Citations

75