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Article ; Online: Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine.

Acevedo-Canabal, Agnes / Grim, Travis W / Schmid, Cullen L / McFague, Nina / Stahl, Edward L / Kennedy, Nicole M / Bannister, Thomas D / Bohn, Laura M

Biomolecules

2023 Volume 13, Issue 6

Abstract: Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum ... ...

Abstract	Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using
MeSH term(s)	Mice ; Animals ; Morphine/pharmacology ; Analgesics, Opioid/pharmacology ; Spiro Compounds ; Fentanyl/pharmacology
Chemical Substances	Morphine (76I7G6D29C) ; Analgesics, Opioid ; ((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine ; Spiro Compounds ; Fentanyl (UF599785JZ)
Language	English
Publishing date	2023-06-02
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13060935
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: G protein signaling-biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists.

Stahl, Edward L / Schmid, Cullen L / Acevedo-Canabal, Agnes / Read, Cai / Grim, Travis W / Kennedy, Nicole M / Bannister, Thomas D / Bohn, Laura M

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 48

Abstract: The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity, and biased agonism. The presentation of ligand bias reflects ... ...

Abstract	The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity, and biased agonism. The presentation of ligand bias reflects selectivity between active states of the receptor, which may result in the display of preferential engagement with one signaling pathway over another. In this study, we provide evidence that the G protein-biased mu opioid receptor (MOR) agonists SR-17018 and SR-14968 stabilize the MOR in a wash-resistant yet antagonist-reversible G protein-signaling state. Furthermore, we demonstrate that these structurally related biased agonists are noncompetitive for radiolabeled MOR antagonist binding, and while they stimulate G protein signaling in mouse brains, partial agonists of this class do not compete with full agonist activation. Importantly, opioid antagonists can readily reverse their effects in vivo. Given that chronic treatment with SR-17018 does not lead to tolerance in several mouse pain models, this feature may be desirable for the development of long-lasting opioid analgesics that remain sensitive to antagonist reversal of respiratory suppression.
MeSH term(s)	Analgesics, Opioid/pharmacology ; Animals ; Benzimidazoles/pharmacology ; GTP-Binding Proteins/metabolism ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Narcotic Antagonists/pharmacology ; Piperidines/pharmacology ; Receptors, G-Protein-Coupled/metabolism ; Receptors, G-Protein-Coupled/physiology ; Receptors, Opioid, mu/agonists ; Receptors, Opioid, mu/metabolism ; Receptors, Opioid, mu/physiology ; Signal Transduction/drug effects ; Signal Transduction/physiology ; beta-Arrestin 2/metabolism
Chemical Substances	Analgesics, Opioid ; Benzimidazoles ; Ligands ; Narcotic Antagonists ; Piperidines ; Receptors, G-Protein-Coupled ; Receptors, Opioid, mu ; beta-Arrestin 2 ; sr-17018 ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2021-11-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2102178118
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Article ; Online: Stolonidiol: Synthesis, Target Identification, and Mechanism for Choline Acetyltransferase Activation.

Mason, Jeremy W / Schmid, Cullen L / Bohn, Laura M / Roush, William R

Journal of the American Chemical Society

2017 Volume 139, Issue 16, Page(s) 5865–5869

Abstract: Stolonidiol, a marine natural product, has been reported to potentiate the activity of choline acetyltransferase (ChAT), the enzyme that produces the neurotransmitter acetylcholine. Here we report the total synthesis of stolonidiol starting from (R)-(+)- ... ...

Abstract	Stolonidiol, a marine natural product, has been reported to potentiate the activity of choline acetyltransferase (ChAT), the enzyme that produces the neurotransmitter acetylcholine. Here we report the total synthesis of stolonidiol starting from (R)-(+)-limonene. To identify the mechanism by which ChAT activity is increased, we sought to identify the biological target of stolonidiol. We show that stolonidiol binds to the phorbol ester binding site of protein kinase C (PKC), induces translocation of PKC to the cell membrane, and activates kinase activity. Furthermore, we confirmed the increase in ChAT activity observed upon treatment of cells with stolonidiol and show that this effect is mediated by PKC. Collectively, our data strongly suggest that PKC activation by stolonidiol is responsible for the resulting potentiation of ChAT activity.
Language	English
Publishing date	2017-04-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.7b01083
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Article ; Online: Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain.

Pantouli, Fani / Grim, Travis W / Schmid, Cullen L / Acevedo-Canabal, Agnes / Kennedy, Nicole M / Cameron, Michael D / Bannister, Thomas D / Bohn, Laura M

Neuropharmacology

2020 Volume 185, Page(s) 108439

Abstract: The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over βarrestin2 recruitment in cellular assays, thereby demonstrating signaling bias. In mice, SR-17018 stimulates GTPγS binding in brainstem and produces ... ...

Abstract	The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over βarrestin2 recruitment in cellular assays, thereby demonstrating signaling bias. In mice, SR-17018 stimulates GTPγS binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.
MeSH term(s)	Animals ; Female ; Male ; Mice ; Analgesics, Opioid/administration & dosage ; Benzimidazoles/administration & dosage ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Tolerance ; Infusion Pumps, Implantable ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Morphine/administration & dosage ; Neuralgia/drug therapy ; Neuralgia/pathology ; Oxycodone/administration & dosage ; Pain Measurement/drug effects ; Pain Measurement/methods ; Piperidines/administration & dosage ; Receptors, Opioid, mu/agonists ; Treatment Outcome
Chemical Substances	Analgesics, Opioid ; Benzimidazoles ; Morphine (76I7G6D29C) ; Oxycodone (CD35PMG570) ; Piperidines ; Receptors, Opioid, mu ; sr-17018
Language	English
Publishing date	2020-12-17
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2020.108439
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Article ; Online: Serotonin receptor signaling and regulation via β-arrestins.

Bohn, Laura M / Schmid, Cullen L

Critical reviews in biochemistry and molecular biology

2010 Volume 45, Issue 6, Page(s) 555–566

Abstract: Serotonin receptors are the product of 15 distinct genes, 14 of which are G protein-coupled receptors. These receptors are expressed in a wide range of cell types, including distinct neuronal populations, and promote diverse functional responses in ... ...

Abstract	Serotonin receptors are the product of 15 distinct genes, 14 of which are G protein-coupled receptors. These receptors are expressed in a wide range of cell types, including distinct neuronal populations, and promote diverse functional responses in multiple organ systems. These receptors are important for mediating the in vivo effects of their cognate neurotransmitter, serotonin, as well as the endogenous tryptamines. In addition, the actions of many drugs are mediated, either directly or indirectly, through serotonin receptors, including antidepressants, antipsychotics, anxiolytics, sleep aids, migraine therapies, gastrointestinal therapeutics and hallucinogenic drugs. It is becoming increasingly evident that serotonin receptors can engage in differential signaling that is determined by the chemical nature of the ligand and that ligands that demonstrate a predilection for inducing a particular signaling cascade are considered to have "functional selectivity". The elucidation of the cellular signaling pathways that mediate the physiological responses to serotonin and other agonists is an active area of investigation and will be an onward-looking focal point for determining how to effectively and selectively promote beneficial serotonergic mimicry while avoiding unwanted clinical side effects. This review highlights the modulation of serotonin 2A, 2C, and four receptors by β-arrestins, which may represent a fulcrum for biasing receptor responsiveness in vivo.
MeSH term(s)	Animals ; Anti-Anxiety Agents/pharmacology ; Antidepressive Agents/pharmacology ; Antipsychotic Agents/pharmacology ; Arrestins/genetics ; Arrestins/metabolism ; Central Nervous System/metabolism ; Hallucinogens/pharmacology ; Humans ; Neurons/drug effects ; Neurons/metabolism ; Peripheral Nervous System/metabolism ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Serotonin/genetics ; Receptors, Serotonin/metabolism ; Serotonin/metabolism ; Serotonin/pharmacology ; Serotonin Receptor Agonists/pharmacology ; Signal Transduction/drug effects ; beta-Arrestins
Chemical Substances	Anti-Anxiety Agents ; Antidepressive Agents ; Antipsychotic Agents ; Arrestins ; Hallucinogens ; Receptors, G-Protein-Coupled ; Receptors, Serotonin ; Serotonin Receptor Agonists ; beta-Arrestins ; Serotonin (333DO1RDJY)
Language	English
Publishing date	2010-10-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1000977-2
ISSN	1549-7798 ; 1381-3455 ; 1040-9238
ISSN (online)	1549-7798
ISSN	1381-3455 ; 1040-9238
DOI	10.3109/10409238.2010.516741
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Article: Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent κ-OR Agonist.

Roach, Jeremy J / Sasano, Yusuke / Schmid, Cullen L / Zaidi, Saheem / Katritch, Vsevolod / Stevens, Raymond C / Bohn, Laura M / Shenvi, Ryan A

ACS central science

2017 Volume 3, Issue 12, Page(s) 1329–1336

Abstract: Salvinorin A (SalA) is a plant metabolite that agonizes the ... ...

Abstract	Salvinorin A (SalA) is a plant metabolite that agonizes the human
Language	English
Publishing date	2017-12-13
Publishing country	United States
Document type	Journal Article
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.7b00488
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Article ; Online: Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a ß-arrestin2/Src/Akt signaling complex in vivo.

Schmid, Cullen L / Bohn, Laura M

The Journal of neuroscience : the official journal of the Society for Neuroscience

2010 Volume 30, Issue 40, Page(s) 13513–13524

Abstract: ... to engage a β-arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-L ...

Abstract	Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT(2A)R). Although serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT(2A)R and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactive N-methyltryptamines by its ability to engage a β-arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-L-tryptophan (5-HTP) induce a head-twitch response in wild-type (WT) mice that is a behavioral proxy for 5-HT(2A)R activation. The response in β-arrestin2 knock-out (βarr2-KO) mice is greatly attenuated until the doses are elevated, at which point, βarr2-KO mice display a head-twitch response that can exceed that of WT mice. Direct administration of N-methyltryptamines also produces a greater response in βarr2-KO mice. Moreover, the inhibition of N-methyltransferase blocks 5-HTP-induced head twitches in βarr2-KO mice, indicating that N-methyltryptamines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a β-arrestin2/phosphoinositide 3-kinase/Src/Akt cascade, whereas N-methyltryptamines do not. Furthermore, disruption of any of the components of this cascade prevents 5-HTP-induced, but not N-methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT(2A)R signaling that is neurotransmitter and β-arrestin2 dependent. This demonstration of agonist-directed 5-HT(2A)R signaling in vivo may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; Animals, Newborn ; Arrestins/genetics ; Arrestins/physiology ; Cells, Cultured ; Frontal Lobe/cytology ; Frontal Lobe/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons/cytology ; Neurons/enzymology ; Neurons/metabolism ; Proto-Oncogene Proteins c-akt/physiology ; Receptor, Serotonin, 5-HT2A/metabolism ; Serotonin/metabolism ; Serotonin/physiology ; Serotonin 5-HT2 Receptor Agonists ; Signal Transduction/physiology ; Synaptic Transmission/physiology ; Tryptamines/metabolism ; Tryptamines/physiology ; beta-Arrestins ; src-Family Kinases/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Arrestins ; Receptor, Serotonin, 5-HT2A ; Serotonin 5-HT2 Receptor Agonists ; Tom1L1 protein, mouse ; Tryptamines ; beta-Arrestins ; Serotonin (333DO1RDJY) ; N-methyltryptamine (6FRL4L3Z7V) ; src-Family Kinases (EC 2.7.10.2) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2010-10-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1665-10.2010
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Article ; Online: G protein signaling-biased agonism at the κ-opioid receptor is maintained in striatal neurons.

Ho, Jo-Hao / Stahl, Edward L / Schmid, Cullen L / Scarry, Sarah M / Aubé, Jeffrey / Bohn, Laura M

Science signaling

2018 Volume 11, Issue 542

Abstract: Biased agonists of G protein-coupled receptors may present a means to refine receptor signaling in a way that separates side effects from therapeutic properties. Several studies have shown that agonists that activate the κ-opioid receptor (KOR) in a ... ...

Abstract	Biased agonists of G protein-coupled receptors may present a means to refine receptor signaling in a way that separates side effects from therapeutic properties. Several studies have shown that agonists that activate the κ-opioid receptor (KOR) in a manner that favors G protein coupling over β-arrestin2 recruitment in cell culture may represent a means to treat pain and itch while avoiding sedation and dysphoria. Although it is attractive to speculate that the bias between G protein signaling and β-arrestin2 recruitment is the reason for these divergent behaviors, little evidence has emerged to show that these signaling pathways diverge in the neuronal environment. We further explored the influence of cellular context on biased agonism at KOR ligand-directed signaling toward G protein pathways over β-arrestin-dependent pathways and found that this bias persists in striatal neurons. These findings advance our understanding of how a G protein-biased agonist signal differs between cell lines and primary neurons, demonstrate that measuring [
MeSH term(s)	Animals ; Animals, Newborn ; Benzeneacetamides/pharmacology ; CHO Cells ; Cell Line, Tumor ; Cells, Cultured ; Corpus Striatum/cytology ; Corpus Striatum/metabolism ; Cricetinae ; Cricetulus ; GTP-Binding Proteins/metabolism ; HEK293 Cells ; Humans ; Mice, Knockout ; Neurons/metabolism ; Pyrrolidines/pharmacology ; Receptors, Opioid, kappa/agonists ; Receptors, Opioid, kappa/genetics ; Receptors, Opioid, kappa/metabolism ; Signal Transduction ; beta-Arrestin 2/genetics ; beta-Arrestin 2/metabolism
Chemical Substances	Benzeneacetamides ; Pyrrolidines ; Receptors, Opioid, kappa ; beta-Arrestin 2 ; GTP-Binding Proteins (EC 3.6.1.-) ; U 69593 (J5S4K6TKTG)
Language	English
Publishing date	2018-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aar4309
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Article: Stolonidiol: Synthesis, Target Identification, and Mechanism for Choline Acetyltransferase Activation

Mason, Jeremy W / Bohn Laura M / Roush William R / Schmid Cullen L

Journal of the American Chemical Society. 2017 Apr. 26, v. 139, no. 16

2017

Abstract	Stolonidiol, a marine natural product, has been reported to potentiate the activity of choline acetyltransferase (ChAT), the enzyme that produces the neurotransmitter acetylcholine. Here we report the total synthesis of stolonidiol starting from (R)-(+)-limonene. To identify the mechanism by which ChAT activity is increased, we sought to identify the biological target of stolonidiol. We show that stolonidiol binds to the phorbol ester binding site of protein kinase C (PKC), induces translocation of PKC to the cell membrane, and activates kinase activity. Furthermore, we confirmed the increase in ChAT activity observed upon treatment of cells with stolonidiol and show that this effect is mediated by PKC. Collectively, our data strongly suggest that PKC activation by stolonidiol is responsible for the resulting potentiation of ChAT activity.
Keywords	acetylcholine ; binding sites ; cell membranes ; choline acetyltransferase ; neurotransmitters ; protein kinase C
Language	English
Dates of publication	2017-0426
Size	p. 5865-5869.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021%2Fjacs.7b01083
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Article ; Online: The effect of quinine in two bottle choice procedures in C57BL6 mice: Opioid preference, somatic withdrawal, and pharmacokinetic outcomes.

Grim, Travis W / Park, Scarlet Jinhong / Schmid, Cullen L / Laprairie, Robert B / Cameron, Michael / Bohn, Laura M

Drug and alcohol dependence

2018 Volume 191, Page(s) 195–202

Abstract: Previous reports assessing morphine effects in two bottle choice (TBC) paradigms often use taste adulterants such as sweeteners (e.g., saccharin) and/or bitterants (e.g., quinine) to demonstrate morphine preference with C57BL6 mice. The effect of these ... ...

Abstract	Previous reports assessing morphine effects in two bottle choice (TBC) paradigms often use taste adulterants such as sweeteners (e.g., saccharin) and/or bitterants (e.g., quinine) to demonstrate morphine preference with C57BL6 mice. The effect of these additional components on the morphine preference of C57BL6 remains poorly understood. Thus, we sought to elucidate the interrelationship of morphine and quinine in the TBC paradigm. As expected, when morphine was included in the opposite bottle from quinine, a preference for the morphine solution was observed. Conversely, when quinine was included in each bottle, or when fentanyl without quinine was used, no preference was observed. All opioid-drinking mice displayed withdrawal signs, and morphine was detectable in plasma and brain. When these results were compared to previous results via conversion to quinine preference scores, quinine was revealed to determine largely the measured morphine preference. Thus, quinine is effective to drive morphine consumption and engender dependence but may confound the ability to measure oral abuse liability of morphine. Together, these results suggest future TBC procedures should consider the effect of quinine upon measured preference for compounds in the opposite bottle, and that excessively high quinine concentrations appear to influence preference more so than the opposite solute when using C57BL6 mice. Alternative conditions to assess oral abuse liability may be necessary to complement and confirm results from TBC experiments utilizing morphine or other opioids.
MeSH term(s)	Analgesics, Opioid/administration & dosage ; Analgesics, Opioid/pharmacokinetics ; Animals ; Brain/drug effects ; Brain/metabolism ; Choice Behavior/drug effects ; Choice Behavior/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Morphine/administration & dosage ; Quinine/administration & dosage ; Quinine/pharmacokinetics ; Saccharin/administration & dosage ; Substance Withdrawal Syndrome/diagnosis ; Substance Withdrawal Syndrome/metabolism ; Taste/drug effects
Chemical Substances	Analgesics, Opioid ; Morphine (76I7G6D29C) ; Quinine (A7V27PHC7A) ; Saccharin (FST467XS7D)
Language	English
Publishing date	2018-08-02
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	519918-9
ISSN	1879-0046 ; 0376-8716
ISSN (online)	1879-0046
ISSN	0376-8716
DOI	10.1016/j.drugalcdep.2018.05.034
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