scholarly journals Divergent profiles of fentanyl withdrawal and associated pain in mice and rats

2020 ◽  
Author(s):  
Olivia Uddin ◽  
Carleigh Jenne ◽  
Megan E. Fox ◽  
Keiko Arakawa ◽  
Asaf Keller ◽  
...  
Keyword(s):  
Thermal Hyperalgesia ◽  
Opioid Withdrawal ◽  
Human Condition ◽  
Model Systems ◽  
Preclinical Models ◽  
Precipitated Withdrawal ◽  
Withdrawal Behaviors ◽  
Illicit Use ◽  
Ongoing Pain ◽  
Rats And Mice

AbstractOpioid abuse has devastating effects on patients, their families, and society. Withdrawal symptoms are severely unpleasant, prolonged, and frequently hinder recovery or lead to relapse. The sharp increase in abuse and overdoses arising from the illicit use of potent and rapidly-acting synthetic opioids, such as fentanyl, highlights the urgency of understanding the withdrawal mechanisms related to these drugs. Progress is impeded by inconsistent reports on opioid withdrawal in different preclinical models. Here, using rats and mice of both sexes, we quantified withdrawal behaviors during spontaneous and naloxone-precipitated withdrawal, following two weeks of intermittent fentanyl exposure. We found that both mice and rats lost weight during exposure and showed increased signs of distress during spontaneous and naloxone precipitated withdrawal. However, these species differed in their expression of withdrawal associated pain, a key contributor to relapse in humans. Spontaneous or ongoing pain was preferentially expressed in rats in both withdrawal conditions, while no change was observed in mice. In contrast, withdrawal associated thermal hyperalgesia was found only in mice. These data suggest that rats and mice diverge in how they experience withdrawal and which aspects of the human condition they most accurately model. These differences highlight each species’ strengths as model systems and can inform experimental design in studies of opioid withdrawal.

scholarly journals Establishing Preclinical Withdrawal Syndrome Symptomatology Following Heroin Self-Administration in Male and Female Rats

2020 ◽  
Author(s):  
Cassandra D. Gipson ◽  
Kelly E. Dunn ◽  
Amanda Bull ◽  
Hanaa Ulangkaya ◽  
Aronee Hossain
Keyword(s):  
Phase 1 ◽  
Opioid Withdrawal ◽  
Female Rats ◽  
Preclinical Models ◽  
Self Administration ◽  
Male And Female ◽  
Somatic Signs ◽  
Male And Female Rats ◽  
Opioid Administration ◽  
Abrupt Discontinuation

AbstractOpioid use disorder (OUD) is a significant health problem, and understanding mechanisms of various aspects of OUD including drug use and withdrawal is important. Preclinical models provide an ideal opportunity to evaluate mechanisms underlying opioid withdrawal. Current models are limited by their reliance upon forced opioid administration, focus on the acute (and not protracted) syndrome, and exclusion of females. In this study, male and female rats self-administered heroin (maintenance dose of 12.5 μg/kg/infusion) opioid withdrawal following abrupt discontinuation was measured. In Phase 1, acute withdrawal symptoms were rated in male and female rats at 0, 16, 48, and 72 hrs following the last self-administration session. Total somatic signs increased until 48 hrs (predominantly in females), and heroin intake positively correlated with total somatic signs at the 48 and 72 hr timepoints. Measures of hyperactivity and anxiety-like behavior increased by 16 and 48 hrs, respectively. In Phase 2, symptoms were assessed at baseline, acute, and protracted (168 and 312 hrs after self-administration) timepoints in a subset of male and female rats from Phase 1. The total number of somatic signs did not differ across timepoints, though females displayed significantly higher body temperature at all timepoints compared to males, indicating sex-specific protracted withdrawal symptomatology. These data provide a thorough characterization of rodent opioid withdrawal symptomatology following self-administration and abrupt discontinuation that serve as a foundation for future studies designed to mimic the human experience, and demonstrate the importance of characterizing acute and protracted withdrawal with sex-specificity in preclinical models of opioid self-administration.

scholarly journals Sphingosine-1-phosphate receptor subtype 1 activation in the central nervous system contributes to morphine withdrawal in rodents

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Timothy M. Doyle ◽  
Mark R. Hutchinson ◽  
Kathryn Braden ◽  
Kali Janes ◽  
Vicky Staikopoulos ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Side Effects ◽  
De Novo ◽  
Morphine Withdrawal ◽  
Sphingolipid Metabolism ◽  
Receptor Subtype ◽  
Precipitated Withdrawal ◽  
Sphingosine 1 Phosphate ◽  
Withdrawal Behaviors ◽  
The Impact

Abstract Opioid therapies for chronic pain are undermined by many adverse side effects that reduce their efficacy and lead to dependence, abuse, reduced quality of life, and even death. We have recently reported that sphingosine-1-phosphate (S1P) 1 receptor (S1PR1) antagonists block the development of morphine-induced hyperalgesia and analgesic tolerance. However, the impact of S1PR1 antagonists on other undesirable side effects of opioids, such as opioid-induced dependence, remains unknown. Here, we demonstrate that naloxone-precipitated morphine withdrawal in mice altered de novo sphingolipid metabolism in the dorsal horn of the spinal cord and increased S1P that accompanied the manifestation of several withdrawal behaviors. Blocking de novo sphingolipid metabolism with intrathecal administration of myriocin, an inhibitor of serine palmitoyltransferase, blocked naloxone-precipitated withdrawal. Noteworthy, we found that competitive (NIBR-15) and functional (FTY720) S1PR1 antagonists attenuated withdrawal behaviors in mice. Mechanistically, at the level of the spinal cord, naloxone-precipitated withdrawal was associated with increased glial activity and formation of the potent inflammatory/neuroexcitatory cytokine interleukin-1β (IL-1β); these events were attenuated by S1PR1 antagonists. These results provide the first molecular insight for the role of the S1P/S1PR1 axis during opioid withdrawal. Our data identify S1PR1 antagonists as potential therapeutics to mitigate opioid-induced dependence and support repurposing the S1PR1 functional antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.

scholarly journals The relationship between pupil diameter and other measures of opioid withdrawal during naloxone precipitated withdrawal

2019 ◽  
Vol 202 ◽  
pp. 111-114
Author(s):  
Cecilia L. Bergeria ◽  
Andrew S. Huhn ◽  
D. Andrew Tompkins ◽  
George E. Bigelow ◽  
Eric C. Strain ◽  
...  
Keyword(s):  
Pupil Diameter ◽  
Opioid Withdrawal ◽  
Precipitated Withdrawal ◽  
The Relationship

Animal models of psychosis

2020 ◽  
pp. 496-506
Author(s):  
Daniel Scott
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Psychiatric Illness ◽  
Behavioral Assessment ◽  
Underlying Disease ◽  
Human Condition ◽  
Model Systems ◽  
Behavioral Assessments ◽  
Validity Measures ◽  
Valid Animal Model

The creation of a valid animal model is of crucial importance to the study of the biological mechanisms underlying disease pathophysiology. This becomes difficult when studying psychiatric illness, most especially psychosis, as humans’ mental state is a strictly internally experienced phenomenon, and thus the biological readout of these conditions is often a behavioral assessment. Therefore, when designing appropriate animal model systems and behavioral assessments for the study of psychiatric illness, it is necessary that appropriate measures be taken to ensure the systems and tasks used fulfill rigorous demands of validity. This chapter discusses different forms of validity, expanding on the classical validity measures of face, predictive, and construct validity. Specific examples of behavioral assessments and animal preparations that adhere to these specific definitions of validity are presented. These include specific experimental paradigms that can be similarly assessed in humans with psychosis and animal models, methods to create an animal preparation based on known psychosis triggers and risk factors, and pharmacological means to demonstrate relevance to the human condition. The chapter argues for a systematic approach to design, verify, and validate an animal model system for research into psychosis specifically, and other psychiatric disorders more generally, based on these different classes of validity.

scholarly journals Resistance to PARP Inhibitors: Lessons from Preclinical Models of BRCA-Associated Cancer

2019 ◽  
Vol 3 (1) ◽  
pp. 235-254 ◽  
Author(s):  
Ewa Gogola ◽  
Sven Rottenberg ◽  
Jos Jonkers
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Parp Inhibitors ◽  
Model Systems ◽  
Basic Knowledge ◽  
Genetic Screens ◽  
Preclinical Models ◽  
Resistant Disease ◽  
Damage Response ◽  
Generation Sequencing

Inhibitors of poly(ADP-ribose) polymerase (PARP) have recently entered the clinic for the treatment of homologous recombination–deficient cancers. Despite the success of this approach, resistance to PARP inhibitors (PARPis) is a clinical hurdle, and it is poorly understood how cancer cells escape the deadly effects of PARPis without restoring BRCA1/2 function. By synergizing the advantages of next-generation sequencing with functional genetic screens in tractable model systems, novel mechanisms providing useful insights into DNA damage response (DDR) have been identified. BRCA1/2 models not only are tools to explore therapy escape mechanisms but also yield basic knowledge about DDR pathways and PARPis’ mechanism of action. Moreover, alterations that render cells resistant to targeted therapies may cause new synthetic dependencies that can be exploited to combat resistant disease.

Mechanical allodynia and thermal hyperalgesia upon acute opioid withdrawal in the neonatal rat

Pain ◽  
2004 ◽  
Vol 110 (1) ◽  
pp. 269-280 ◽  
Author(s):  
Sarah M Sweitzer ◽  
Caroline P Allen ◽  
Maurice H Zissen ◽  
Joan J Kendig
Keyword(s):  
Mechanical Allodynia ◽  
Thermal Hyperalgesia ◽  
Opioid Withdrawal ◽  
Neonatal Rat

The podocyte as a direct target of glucocorticoids in nephrotic syndrome

2021 ◽  
Author(s):  
Martijn van den Broek ◽  
Bart Smeets ◽  
Michiel F Schreuder ◽  
Jitske Jansen
Keyword(s):  
Nephrotic Syndrome ◽  
Inflammatory Responses ◽  
Human Condition ◽  
Model Systems ◽  
Comprehensive Overview ◽  
Beneficial Effects ◽  
Podocyte Loss ◽  
Patients Experience ◽  
Related Proteins ◽  
Multiple Relapses

Abstract Nephrotic syndrome (NS) is characterized by massive proteinuria; podocyte loss or altered function is a central event in its pathophysiology. Treatment with glucocorticoids is the mainstay of therapy. However, many patients experience one or multiple relapses and prolonged use may be associated with severe adverse effects. Recently, the beneficial effects of glucocorticoids have been attributed to a direct effect on podocytes in addition to the well-known immunosuppressive effects. The molecular effects of glucocorticoid action have been studied using animal and cell models of NS. This review provides a comprehensive overview of different molecular mediators regulated by glucocorticoids including an overview of the model systems that were used to study them. Glucocorticoids are described to stimulate podocyte recovery by restoring pro-survival signaling of slit diaphragm related proteins and limiting inflammatory responses. Of special interest is the effect of glucocorticoids on stabilizing the cytoskeleton of podocytes, since these effects are also described for other therapeutic agents used in NS, such as cyclosporin. Current models provide much insight, but do not fully recapitulate the human condition since the pathophysiology underlying NS is poorly understood. New and promising models include the glomerulus-on-a-chip and kidney organoids, which have the potential to be further developed into functional NS models in the future.

scholarly journals Cyclical aggregation extends in vitro expansion potential of human mesenchymal stem cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Brent M. Bijonowski ◽  
Xuegang Yuan ◽  
Richard Jeske ◽  
Yan Li ◽  
Samuel C. Grant
Keyword(s):  
Stem Cell ◽  
Clinical Relevance ◽  
Human Mesenchymal Stem Cells ◽  
Model Systems ◽  
Therapeutic Effects ◽  
In Vitro Aging ◽  
Animal Disease Models ◽  
In Vitro Expansion ◽  
Rats And Mice

AbstractMesenchymal stem cell (MSC)-based therapy has shown great promises in various animal disease models. However, this therapeutic potency has not been well claimed when applied to human clinical trials. This is due to both the availability of MSCs at the time of administration and lack of viable expansion strategies. MSCs are very susceptible to in vitro culture environment and tend to adapt the microenvironment which could lead to cellular senescence and aging. Therefore, extended in vitro expansion induces loss of MSC functionality and its clinical relevance. To combat this effect, this work assessed a novel cyclical aggregation as a means of expanding MSCs to maintain stem cell functionality. The cyclical aggregation consists of an aggregation phase and an expansion phase by replating the dissociated MSC aggregates onto planar tissue culture surfaces. The results indicate that cyclical aggregation maintains proliferative capability, stem cell proteins, and clonogenicity, and prevents the acquisition of senescence. To determine why aggregation was responsible for this phenomenon, the integrated stress response pathway was probed with salubrial and GSK-2606414. Treatment with salubrial had no significant effect, while GSK-2606414 mitigated the effects of aggregation leading to in vitro aging. This method holds the potential to increase the clinical relevance of MSC therapeutic effects from small model systems (such as rats and mice) to humans, and may open the potential of patient-derived MSCs for treatment thereby removing the need for immunosuppression.

scholarly journals TMIC-26. PRECLINICAL MODEL SYSTEMS OF GLIOBLASTOMA REVEAL MICROENVIRONMENTAL PROGRAMS AND DEPENDENCIES IN PATIENT TUMORS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi253-vi253
Author(s):  
Nicholas Bayley ◽  
Christopher Tse ◽  
Lynn Baufeld ◽  
Laura Gosa ◽  
Weihong Yan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Functional Divergence ◽  
Critical Role ◽  
Gene Expression Signature ◽  
Model Systems ◽  
Preclinical Model ◽  
Preclinical Models ◽  
Molecular Features ◽  
The Brain

Abstract Patient-derived model systems serve as a platform for translational research representing the heterogeneity of human cancers, and their success in recapitulating disease-driving genomic alterations is well-documented. While recent studies have demonstrated genomic and functional divergence in patient-derived models with passaging, the need for accurate preclinical models remains. Glioblastoma (GBM) is the most common and aggressive primary brain tumor, and thus far preclinical models have failed to consistently replicate the responses found in patients. We therefore aimed to evaluate the multi-omic fidelity of low-passage GBM model systems across in vitro and in vivo environments and to elucidate the molecular features in which they differ. To this end we established a biobank of glioma direct-from-patient orthotopic xenograft (GliomaPDOX) models and primary gliomasphere cultures (GSCs) and performed whole-exome and RNA sequencing of over 40 purified patient tumors and their matched GliomaPDOXs and GSCs to facilitate paired comparisons across a gradient of full tumor microenvironment (TME) presence. We observed global genomic and transcriptomic fidelity in both systems, but specific programmatic gene expression differences associated with cell-cell interactions in the brain TME, glial cell identity, and in vitro GSC-forming ability. GSCs and GSC-forming ability are strongly associated with an astrocytic gene expression signature, while more stem-like and oligodendrocytic patient tumors including IDH- and H3F3A-mutant GBMs more successfully engraft in GliomaPDOXs. This result implicates the brain TME as a support system for these more stem/oligo-like tumors. Transcription factor network analysis identified regulators of the NOTCH and MYC pathways as strongly enriched in this subgroup of patient tumors and their derivative xenografts, and provides potential targets for therapeutic intervention in near future experiments. Collectively, these findings underline the critical role of the TME in defining GBM cell state, reveal the heterogeneity of TME dependence across patient tumors, and link this dependency to therapeutically actionable molecular features.

scholarly journals Naloxone precipitated withdrawal increases dopamine release in the dorsal striatum of opioid dependent men

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ehsan Shokri-Kojori ◽  
Gene-Jack Wang ◽  
Nora D. Volkow
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Brain Function ◽  
Dorsal Striatum ◽  
Opioid Use Disorder ◽  
Opioid Withdrawal ◽  
Opioid Antagonist ◽  
Opioid Use ◽  
Precipitated Withdrawal ◽  
Da Release

AbstractDopamine (DA) neurotransmission is critical in the neurobiology of reward and aversion, but its contribution to the aversive state of opioid withdrawal remains unknown in humans. To address this, we used updated voxelwise methods and retrospectively analyzed a [11C]raclopride-PET dataset to measure D2/3 receptor availability and relative cerebral blood flow (R1) in male opioid use disorder (OUD) participants (n = 10) during placebo and acute opioid withdrawal conditions. We found that acute withdrawal precipitated by the opioid antagonist naloxone significantly increased dorsal striatal DA release in OUD participants (pFWE < 0.05). Net changes in striatal DA were significantly correlated with a subjective index of withdrawal aversion such that greater DA increases were associated with more aversive responses (r(8) = 0.82, p < 0.005). Withdrawal also affected brain function, as indexed by increases in relative cerebral blood flow in the insula and putamen (pFWE < 0.05). Our findings are different from preclinical studies that have primarily reported decreases in ventral striatal DA during naloxone precipitated withdrawal, whereas this effect was not significant in OUD participants (p = 0.79). In sum, we provide evidence for the contribution of increases in dorsal striatal DA to the aversive state of naloxone precipitated withdrawal in humans.

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